Nutrient chapter

Fisetin

Fisetin is a plant flavonol with effects that depend on concentration, cell state and metabolism. This collection connects glutathione regulation, iron and copper chemistry, GPX4-dependent lipid protection, senescence, nutrient-sensing kinases and drug metabolism. Fisetin, geraldol and conjugates remain separate entities. Human trials, chemical reactions, cell experiments and animal outcomes retain their own evidence limits; reduced senescence markers do not automatically mean senescent-cell killing.

74 recorded mechanisms · 11 availability situations · 8 preserved sources. Draft and verified records are labeled separately.

Read recorded mechanisms Open recursive mind map

The mechanisms

What the sources say this nutrient does, one relationship at a time. Plain wording comes first; the technical statement follows.

Ten human liver samples methylated fisetin; the reported mean activity was 183 +/- 15 pmol/min/mg and the apparent Km was 8.6 micromolar.
Human liver fisetin-methylating activity → Fisetin source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Ex vivo human liver enzyme assays.
limitations
The abstract does not resolve the responsible enzyme isoform or whole-body methyl-donor demand.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Human liver can chemically modify fisetin.
primary_references
Methylation of quercetin and fisetin, flavonoids widely distributed in edible vegetables, fruits and wine, by human liver. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12051572/ · DOI 10.5414/cpp40207
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 16–22
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Ex vivo human liver enzyme assays. · source_derived_draft · unverified_draft
## fisetin-human-methylation Human liver can chemically modify fisetin. Ten human liver samples methylated fisetin; the reported mean activity was 183 +/- 15 pmol/min/mg and the apparent Km was 8.6 micromolar. Model: Ex vivo human liver enzyme assays. Limitations: The abstract does not resolve the responsible enzyme isoform or whole-body methyl-donor demand. Evidence access: Primary abstract Methylation of quercetin and fisetin, flavonoids widely distributed in edible vegetables, fruits and wine, by human liver. · 2002 · https://pubmed.ncbi.nlm.nih.gov/12051572/ · DOI 10.5414/cpp40207
Complete structured claim and evidence
After 223 mg/kg intraperitoneal fisetin in mice, chromatography and mass spectrometry identified geraldol as a methoxylated metabolite.
Fisetin → Geraldol / 3-prime-O-methylfisetin source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse disposition experiment; authentic standard comparison.
limitations
High injected animal exposure; not human oral pharmacokinetics.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
The parent compound becomes a distinct molecule.
primary_references
Fisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21840301/ · DOI 10.1016/j.bcp.2011.07.097
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse disposition experiment; authentic standard comparison. · source_derived_draft · unverified_draft
## fisetin-mouse-geraldol The parent compound becomes a distinct molecule. After 223 mg/kg intraperitoneal fisetin in mice, chromatography and mass spectrometry identified geraldol as a methoxylated metabolite. Model: Mouse disposition experiment; authentic standard comparison. Limitations: High injected animal exposure; not human oral pharmacokinetics. Evidence access: Primary abstract Fisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21840301/ · DOI 10.1016/j.bcp.2011.07.097
Complete structured claim and evidence
The mouse disposition study detected a fisetin glucuronide and a glucuronide of geraldol.
Fisetin → Fisetin glucuronides, unresolved positional pool source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse plasma metabolite identification after intraperitoneal dosing.
limitations
Positional conjugate identities remain unresolved here.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Further conjugation changes both the parent and metabolite.
primary_references
Fisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21840301/ · DOI 10.1016/j.bcp.2011.07.097
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 32–38
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse plasma metabolite identification after intraperitoneal dosing. · source_derived_draft · unverified_draft
## fisetin-mouse-conjugates Further conjugation changes both the parent and metabolite. The mouse disposition study detected a fisetin glucuronide and a glucuronide of geraldol. Model: Mouse plasma metabolite identification after intraperitoneal dosing. Limitations: Positional conjugate identities remain unresolved here. Evidence access: Primary abstract Fisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21840301/ · DOI 10.1016/j.bcp.2011.07.097
Complete structured claim and evidence
Geraldol reached higher tumor concentrations than fisetin in the mouse Lewis lung tumor experiment.
Geraldol / 3-prime-O-methylfisetin → Geraldol exposure in mouse Lewis lung tumors source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse tumor distribution after fisetin administration.
limitations
Distribution does not prove the metabolite explains every anticancer response.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A metabolite may reach a target differently.
primary_references
Fisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21840301/ · DOI 10.1016/j.bcp.2011.07.097
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 40–46
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse tumor distribution after fisetin administration. · source_derived_draft · unverified_draft
## fisetin-geraldol-tumor A metabolite may reach a target differently. Geraldol reached higher tumor concentrations than fisetin in the mouse Lewis lung tumor experiment. Model: Mouse tumor distribution after fisetin administration. Limitations: Distribution does not prove the metabolite explains every anticancer response. Evidence access: Primary abstract Fisetin disposition and metabolism in mice: Identification of geraldol as an active metabolite. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21840301/ · DOI 10.1016/j.bcp.2011.07.097
Complete structured claim and evidence
Mouse absolute oral fisetin bioavailability was reported as 7.8% at 100 mg/kg and 31.7% at 200 mg/kg; circulating geraldol exceeded parent exposure.
Fisetin → Mouse oral fisetin bioavailability source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse oral/intravenous LC-MS/MS pharmacokinetic study.
limitations
These are mouse regimen-specific estimates, not human absorption percentages.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Exposure did not scale as a simple fixed fraction of dose.
primary_references
Identification of absolute conversion to geraldol from fisetin and pharmacokinetics in mouse. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27810278/ · DOI 10.1016/j.jchromb.2016.10.034
trigger_kind
biomarker_context Imported condition classification; unverified.
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse oral/intravenous LC-MS/MS pharmacokinetic study. · source_derived_draft · unverified_draft
## fisetin-mouse-oral-exposure Exposure did not scale as a simple fixed fraction of dose. Mouse absolute oral fisetin bioavailability was reported as 7.8% at 100 mg/kg and 31.7% at 200 mg/kg; circulating geraldol exceeded parent exposure. Model: Mouse oral/intravenous LC-MS/MS pharmacokinetic study. Limitations: These are mouse regimen-specific estimates, not human absorption percentages. Evidence access: Primary abstract Identification of absolute conversion to geraldol from fisetin and pharmacokinetics in mouse. · 2016 · https://pubmed.ncbi.nlm.nih.gov/27810278/ · DOI 10.1016/j.jchromb.2016.10.034
Complete structured claim and evidence
After 30 mg/kg intravenous fisetin in rats, plasma AUC ratios for free fisetin, glucuronides and sulfates were approximately 1:6:21.
Fisetin → Fisetin sulfates, unresolved positional pool source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Male Sprague-Dawley rats; phase-II analytical pools.
limitations
No particular human SULT or UGT isoform is established by this result.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Most measured circulating material was conjugated.
primary_references
Pharmacokinetics and Biliary Excretion of Fisetin in Rats. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29862816/ · DOI 10.1021/acs.jafc.8b00917
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Male Sprague-Dawley rats; phase-II analytical pools. · source_derived_draft · unverified_draft
## fisetin-rat-conjugate-dominance Most measured circulating material was conjugated. After 30 mg/kg intravenous fisetin in rats, plasma AUC ratios for free fisetin, glucuronides and sulfates were approximately 1:6:21. Model: Male Sprague-Dawley rats; phase-II analytical pools. Limitations: No particular human SULT or UGT isoform is established by this result. Evidence access: Primary abstract Pharmacokinetics and Biliary Excretion of Fisetin in Rats. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29862816/ · DOI 10.1021/acs.jafc.8b00917
Complete structured claim and evidence
Rat bile contained mainly sulfated fisetin metabolites; the study also implicated P-glycoprotein in fisetin biliary excretion.
Rat biliary export of fisetin-related compounds → Fisetin sulfates, unresolved positional pool source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Cannulated rat bile-duct pharmacokinetic study.
limitations
The reported AUC-based biliary ratio is not a fraction of dose recovered; transporter isoform was not resolved in the abstract.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Transport and conjugation shape elimination.
primary_references
Pharmacokinetics and Biliary Excretion of Fisetin in Rats. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29862816/ · DOI 10.1021/acs.jafc.8b00917
transport_effect
lowers Biliary excretion of sulfated fisetin metabolites, which removes them from the body compartment the chapter follows.
transport_pool
the hepatocyte and the systemic circulation Biliary excretion of sulfated fisetin metabolites, which removes them from the body compartment the chapter follows.
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cannulated rat bile-duct pharmacokinetic study. · source_derived_draft · unverified_draft
## fisetin-rat-biliary-clearance Transport and conjugation shape elimination. Rat bile contained mainly sulfated fisetin metabolites; the study also implicated P-glycoprotein in fisetin biliary excretion. Model: Cannulated rat bile-duct pharmacokinetic study. Limitations: The reported AUC-based biliary ratio is not a fraction of dose recovered; transporter isoform was not resolved in the abstract. Evidence access: Primary abstract Pharmacokinetics and Biliary Excretion of Fisetin in Rats. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29862816/ · DOI 10.1021/acs.jafc.8b00917
Complete structured claim and evidence
In a 15-person crossover study, 1000 mg FF-20 containing 192 mg fisetin produced a reported 26.9-fold higher 12-hour parent AUC than 1000 mg unformulated material.
FF-20 fisetin micelle/fenugreek-galactomannan formulation → Human plasma unconjugated fisetin exposure source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Single-dose healthy-volunteer study; 10-day washout; unformulated product contained approximately 982 mg fisetin.
limitations
Product-specific comparison, not demonstrated clinical superiority or a general effect of dietary fiber.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Formulation changed exposure despite less fisetin in the tested product.
primary_references
Enhanced bioavailability and pharmacokinetics of a novel hybrid-hydrogel formulation of fisetin orally administered in healthy individuals: a randomised double-blinded comparative crossover study. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36304817/ · DOI 10.1017/jns.2022.72
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Single-dose healthy-volunteer study; 10-day washout; unformulated product contained approximately 982 mg fisetin. · source_derived_draft · unverified_draft
## fisetin-human-formulation Formulation changed exposure despite less fisetin in the tested product. In a 15-person crossover study, 1000 mg FF-20 containing 192 mg fisetin produced a reported 26.9-fold higher 12-hour parent AUC than 1000 mg unformulated material. Model: Single-dose healthy-volunteer study; 10-day washout; unformulated product contained approximately 982 mg fisetin. Limitations: Product-specific comparison, not demonstrated clinical superiority or a general effect of dietary fiber. Evidence access: Primary full text Enhanced bioavailability and pharmacokinetics of a novel hybrid-hydrogel formulation of fisetin orally administered in healthy individuals: a randomised double-blinded comparative crossover study. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36304817/ · DOI 10.1017/jns.2022.72
Complete structured claim and evidence
Geraldol was measured after oral fisetin in the human crossover study; its exposure relative to parent differed between formulations.
Fisetin → Geraldol / 3-prime-O-methylfisetin source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Unconjugated parent and geraldol LC-MS/MS measurements.
limitations
Not a complete metabolite balance; altered ratios do not identify the causal absorption or metabolism step.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Human measurements confirm that parent exposure alone is incomplete.
primary_references
Enhanced bioavailability and pharmacokinetics of a novel hybrid-hydrogel formulation of fisetin orally administered in healthy individuals: a randomised double-blinded comparative crossover study. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36304817/ · DOI 10.1017/jns.2022.72
trigger_kind
biomarker_context Imported condition classification; unverified.
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 80–86
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Unconjugated parent and geraldol LC-MS/MS measurements. · source_derived_draft · unverified_draft
## fisetin-human-geraldol-exposure Human measurements confirm that parent exposure alone is incomplete. Geraldol was measured after oral fisetin in the human crossover study; its exposure relative to parent differed between formulations. Model: Unconjugated parent and geraldol LC-MS/MS measurements. Limitations: Not a complete metabolite balance; altered ratios do not identify the causal absorption or metabolism step. Evidence access: Primary abstract Enhanced bioavailability and pharmacokinetics of a novel hybrid-hydrogel formulation of fisetin orally administered in healthy individuals: a randomised double-blinded comparative crossover study. · 2022 · https://pubmed.ncbi.nlm.nih.gov/36304817/ · DOI 10.1017/jns.2022.72
Complete structured claim and evidence
Fisetin reversibly inhibited purified human GSTA1-1 with IC50 1.2 +/- 0.1 micromolar; inhibition was mixed toward glutathione and noncompetitive toward CDNB.
Fisetin → Human glutathione S-transferase A1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Purified human enzyme kinetics.
limitations
CDNB probe assay, not proven human chemosensitization or global detoxification failure.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A compound that supports a glutathione pool can also inhibit an enzyme using it.
primary_references
The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33806779/ · DOI 10.3390/metabo11030190
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 88–94
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Purified human enzyme kinetics. · source_derived_draft · unverified_draft
## fisetin-gsta1-inhibition A compound that supports a glutathione pool can also inhibit an enzyme using it. Fisetin reversibly inhibited purified human GSTA1-1 with IC50 1.2 +/- 0.1 micromolar; inhibition was mixed toward glutathione and noncompetitive toward CDNB. Model: Purified human enzyme kinetics. Limitations: CDNB probe assay, not proven human chemosensitization or global detoxification failure. Evidence access: Primary abstract The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33806779/ · DOI 10.3390/metabo11030190
Complete structured claim and evidence
Fisetin reduced GSTA1 mRNA and protein in proliferating human Caco-2 cells.
Fisetin → Human glutathione S-transferase A1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human colorectal adenocarcinoma cell culture.
limitations
Cell state matters; the proposed binding-site location was based on modeling.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Expression and direct enzyme inhibition are separate observations.
primary_references
The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33806779/ · DOI 10.3390/metabo11030190
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human colorectal adenocarcinoma cell culture. · source_derived_draft · unverified_draft
## fisetin-gsta1-expression Expression and direct enzyme inhibition are separate observations. Fisetin reduced GSTA1 mRNA and protein in proliferating human Caco-2 cells. Model: Human colorectal adenocarcinoma cell culture. Limitations: Cell state matters; the proposed binding-site location was based on modeling. Evidence access: Primary abstract The Interaction of the Flavonoid Fisetin with Human Glutathione Transferase A1-1. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33806779/ · DOI 10.3390/metabo11030190
Complete structured claim and evidence
In the mouse-cell study, fisetin increased Nrf2 stability and Nrf2-dependent transcription.
Fisetin → Mouse Nrf2 / Nfe2l2 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Primary abstract plus PubMed mouse-protein indexing.
limitations
No direct Nrf2 binding site or specific KEAP1 reaction established here.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Stress-defense transcription can stay active for longer.
primary_references
Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23618921/ · DOI 10.1016/j.bcp.2013.04.010
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Primary abstract plus PubMed mouse-protein indexing. · source_derived_draft · unverified_draft
## fisetin-nrf2-stability Stress-defense transcription can stay active for longer. In the mouse-cell study, fisetin increased Nrf2 stability and Nrf2-dependent transcription. Model: Primary abstract plus PubMed mouse-protein indexing. Limitations: No direct Nrf2 binding site or specific KEAP1 reaction established here. Evidence access: Primary abstract Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23618921/ · DOI 10.1016/j.bcp.2013.04.010
Complete structured claim and evidence
Fisetin increased ATF4 stability through a kinase-dependent process in the mouse-cell study.
Fisetin → Mouse activating transcription factor 4 / Atf4 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Protein-stability and kinase-perturbation experiments.
limitations
Kinase dependence does not identify one specific kinase.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A second regulator contributes through a different mechanism.
primary_references
Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23618921/ · DOI 10.1016/j.bcp.2013.04.010
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Protein-stability and kinase-perturbation experiments. · source_derived_draft · unverified_draft
## fisetin-atf4-stability A second regulator contributes through a different mechanism. Fisetin increased ATF4 stability through a kinase-dependent process in the mouse-cell study. Model: Protein-stability and kinase-perturbation experiments. Limitations: Kinase dependence does not identify one specific kinase. Evidence access: Primary abstract Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23618921/ · DOI 10.1016/j.bcp.2013.04.010
Complete structured claim and evidence
ATF4 siRNA reduced the fisetin-associated basal glutathione increase; Nrf2 siRNA did not have the same basal requirement.
Mouse activating transcription factor 4 / Atf4 → Mouse-cell basal glutathione response to fisetin source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse-cell transcription-factor silencing.
limitations
Baseline and oxidative-stress settings are distinct.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Baseline glutathione regulation depended more on ATF4.
primary_references
Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23618921/ · DOI 10.1016/j.bcp.2013.04.010
trigger_kind
machinery_impairment Imported condition classification; unverified.
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 120–126
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse-cell transcription-factor silencing. · source_derived_draft · unverified_draft
## fisetin-atf4-basal-dependence Baseline glutathione regulation depended more on ATF4. ATF4 siRNA reduced the fisetin-associated basal glutathione increase; Nrf2 siRNA did not have the same basal requirement. Model: Mouse-cell transcription-factor silencing. Limitations: Baseline and oxidative-stress settings are distinct. Evidence access: Primary abstract Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23618921/ · DOI 10.1016/j.bcp.2013.04.010
Complete structured claim and evidence
Under oxidative stress, siRNA experiments implicated both Nrf2 and ATF4 in the mouse-cell glutathione response to fisetin.
Mouse Nrf2 / Nfe2l2 → Mouse activating transcription factor 4 / Atf4 source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Mouse-cell gene-silencing comparisons.
limitations
Cooperation in this assay is not proof of universal transcriptional synergy.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
The cell relies on both regulators during stress.
primary_references
Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23618921/ · DOI 10.1016/j.bcp.2013.04.010
trigger_kind
machinery_impairment Imported condition classification; unverified.
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 128–134
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse-cell gene-silencing comparisons. · source_derived_draft · unverified_draft
## fisetin-stress-cooperation The cell relies on both regulators during stress. Under oxidative stress, siRNA experiments implicated both Nrf2 and ATF4 in the mouse-cell glutathione response to fisetin. Model: Mouse-cell gene-silencing comparisons. Limitations: Cooperation in this assay is not proof of universal transcriptional synergy. Evidence access: Primary abstract Concurrent regulation of the transcription factors Nrf2 and ATF4 mediates the enhancement of glutathione levels by the flavonoid fisetin. · 2013 · https://pubmed.ncbi.nlm.nih.gov/23618921/ · DOI 10.1016/j.bcp.2013.04.010
Complete structured claim and evidence
Buffered chemical assays identified 1:1 and 1:2 iron-fisetin complexes with pH-dependent coordination sites.
Fisetin → Fisetin-iron complexes, stoichiometry and pH specified source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Spectroscopy, competition assays and structural calculations.
limitations
Fisetin bound iron less strongly than EDTA and citrate under tested conditions; no human iron-depletion outcome measured.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
The same molecule binds metal differently as conditions change.
primary_references
Comparative spectroscopic and mechanistic study of chelation properties of fisetin with iron in aqueous buffered solutions. Implications on in vitro antioxidant activity. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21431152/ · DOI 10.1039/c0dt01834a
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Spectroscopy, competition assays and structural calculations. · source_derived_draft · unverified_draft
## fisetin-iron-chelation The same molecule binds metal differently as conditions change. Buffered chemical assays identified 1:1 and 1:2 iron-fisetin complexes with pH-dependent coordination sites. Model: Spectroscopy, competition assays and structural calculations. Limitations: Fisetin bound iron less strongly than EDTA and citrate under tested conditions; no human iron-depletion outcome measured. Evidence access: Primary abstract Comparative spectroscopic and mechanistic study of chelation properties of fisetin with iron in aqueous buffered solutions. Implications on in vitro antioxidant activity. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21431152/ · DOI 10.1039/c0dt01834a
Complete structured claim and evidence
A prepared 1:2 copper(II):fisetin complex cleaved and degraded DNA in chemical assays.
Fisetin-copper(II) complexes, stoichiometry specified → DNA cleavage by prepared fisetin-copper complexes source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
DNA electrophoresis and spectroscopic assays.
limitations
Prepared complex exposure is not equivalent to eating copper-containing food with fisetin.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Metal binding does not guarantee antioxidant protection.
primary_references
Physicochemical, antioxidant, DNA cleaving properties and antimicrobial activity of fisetin-copper chelates. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29247867/ · DOI 10.1016/j.jinorgbio.2017.12.006
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · DNA electrophoresis and spectroscopic assays. · source_derived_draft · unverified_draft
## fisetin-copper-dna-chemistry Metal binding does not guarantee antioxidant protection. A prepared 1:2 copper(II):fisetin complex cleaved and degraded DNA in chemical assays. Model: DNA electrophoresis and spectroscopic assays. Limitations: Prepared complex exposure is not equivalent to eating copper-containing food with fisetin. Evidence access: Primary abstract Physicochemical, antioxidant, DNA cleaving properties and antimicrobial activity of fisetin-copper chelates. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29247867/ · DOI 10.1016/j.jinorgbio.2017.12.006
Complete structured claim and evidence
At 5 micromolar, fisetin limited iron- or copper-potentiated glutathione loss and cell death in glutamate-challenged mouse HT22 cells.
Fisetin → Mouse HT22 cellular glutathione content source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Mouse HT22 cells; separately added FeCl2/CuCl2, 0.5-10 micromolar.
limitations
Not a dietary deficiency experiment or evidence of systemic metal removal.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Protection depended on the way oxidative stress was induced.
primary_references
Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33187316/ · DOI 10.3390/antiox9111113
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 152–158
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse HT22 cells; separately added FeCl2/CuCl2, 0.5-10 micromolar. · source_derived_draft · unverified_draft
## fisetin-metal-gsh-protection Protection depended on the way oxidative stress was induced. At 5 micromolar, fisetin limited iron- or copper-potentiated glutathione loss and cell death in glutamate-challenged mouse HT22 cells. Model: Mouse HT22 cells; separately added FeCl2/CuCl2, 0.5-10 micromolar. Limitations: Not a dietary deficiency experiment or evidence of systemic metal removal. Evidence access: Primary full text Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33187316/ · DOI 10.3390/antiox9111113
Complete structured claim and evidence
In mouse HT22 cells, added iron reduced fisetin-induced nuclear Nrf2 and ATF4 from an iron:fisetin ratio of 0.5:1; copper did not do so in the tested range.
Ferrous iron → Mouse Nrf2 / Nfe2l2 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
5 micromolar fisetin with FeCl2/CuCl2 titration.
limitations
Cell-culture ratio, not a clinical spacing rule for supplements.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Iron weakened the signaling response under these conditions.
primary_references
Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33187316/ · DOI 10.3390/antiox9111113
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 160–166
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 5 micromolar fisetin with FeCl2/CuCl2 titration. · source_derived_draft · unverified_draft
## fisetin-iron-signaling-antagonism Iron weakened the signaling response under these conditions. In mouse HT22 cells, added iron reduced fisetin-induced nuclear Nrf2 and ATF4 from an iron:fisetin ratio of 0.5:1; copper did not do so in the tested range. Model: 5 micromolar fisetin with FeCl2/CuCl2 titration. Limitations: Cell-culture ratio, not a clinical spacing rule for supplements. Evidence access: Primary full text Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33187316/ · DOI 10.3390/antiox9111113
Complete structured claim and evidence
With RSL3-mediated GPX4 inhibition, 5 micromolar fisetin enhanced iron-potentiated HT22 toxicity at iron concentrations of 2.5 micromolar or higher.
Fisetin → Mouse HT22 injury during RSL3 plus iron exposure source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Mouse cells; pharmacological GPX4 inhibition plus iron.
limitations
Not proof that fisetin worsens ordinary selenium deficiency; RSL3 and dietary selenium shortage differ.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Protection can fail when a different defense step is blocked.
primary_references
Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33187316/ · DOI 10.3390/antiox9111113
trigger_kind
machinery_impairment Imported condition classification; unverified.
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 168–174
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse cells; pharmacological GPX4 inhibition plus iron. · source_derived_draft · unverified_draft
## fisetin-gpx4-block-metal-injury Protection can fail when a different defense step is blocked. With RSL3-mediated GPX4 inhibition, 5 micromolar fisetin enhanced iron-potentiated HT22 toxicity at iron concentrations of 2.5 micromolar or higher. Model: Mouse cells; pharmacological GPX4 inhibition plus iron. Limitations: Not proof that fisetin worsens ordinary selenium deficiency; RSL3 and dietary selenium shortage differ. Evidence access: Primary full text Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33187316/ · DOI 10.3390/antiox9111113
Complete structured claim and evidence
Nrf2 siRNA weakened fisetin suppression of nitric oxide and IL-6, but not TNF-alpha to the same extent, in LPS-treated mouse BV2 cells.
Mouse Nrf2 / Nfe2l2 → Fisetin-associated suppression of inflammatory output in mouse BV2 cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Mouse microglial cells; Nrf2 knockdown and metal comparisons.
limitations
Endpoint-specific response; not total suppression of immunity.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Even inflammatory outputs had different dependencies.
primary_references
Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33187316/ · DOI 10.3390/antiox9111113
trigger_kind
machinery_impairment Imported condition classification; unverified.
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 176–182
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse microglial cells; Nrf2 knockdown and metal comparisons. · source_derived_draft · unverified_draft
## fisetin-microglial-nrf2-dependence Even inflammatory outputs had different dependencies. Nrf2 siRNA weakened fisetin suppression of nitric oxide and IL-6, but not TNF-alpha to the same extent, in LPS-treated mouse BV2 cells. Model: Mouse microglial cells; Nrf2 knockdown and metal comparisons. Limitations: Endpoint-specific response; not total suppression of immunity. Evidence access: Primary full text Modulation of the Neuroprotective and Anti-inflammatory Activities of the Flavonol Fisetin by the Transition Metals Iron and Copper. · 2020 · https://pubmed.ncbi.nlm.nih.gov/33187316/ · DOI 10.3390/antiox9111113
Complete structured claim and evidence
Fisetin selectively induced apoptosis in senescent human HUVECs while sparing proliferating cells in the reported irradiation model.
Fisetin → Apoptosis of senescent human HUVECs, induction specified source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Human endothelial cultures; apoptosis and viability assays.
limitations
Not a demonstration of senescent-cell removal throughout a human body.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Some senescent cells were selectively vulnerable.
primary_references
New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28273655/ · DOI 10.18632/aging.101202
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 184–190
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human endothelial cultures; apoptosis and viability assays. · source_derived_draft · unverified_draft
## fisetin-huvec-senolysis Some senescent cells were selectively vulnerable. Fisetin selectively induced apoptosis in senescent human HUVECs while sparing proliferating cells in the reported irradiation model. Model: Human endothelial cultures; apoptosis and viability assays. Limitations: Not a demonstration of senescent-cell removal throughout a human body. Evidence access: Primary full text New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28273655/ · DOI 10.18632/aging.101202
Complete structured claim and evidence
Fisetin was not senolytic in the tested senescent human IMR90 fibroblasts or primary preadipocytes.
Fisetin → Senescent human IMR90/preadipocyte viability in the irradiation study source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Same senolytic screening study as the HUVEC result.
limitations
Different cells and later etoposide models are not automatic scientific contradictions.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Cell type and induction method limit the senolytic label.
primary_references
New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28273655/ · DOI 10.18632/aging.101202
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 192–198
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same senolytic screening study as the HUVEC result. · source_derived_draft · unverified_draft
## fisetin-senolysis-selectivity-null Cell type and induction method limit the senolytic label. Fisetin was not senolytic in the tested senescent human IMR90 fibroblasts or primary preadipocytes. Model: Same senolytic screening study as the HUVEC result. Limitations: Different cells and later etoposide models are not automatic scientific contradictions. Evidence access: Primary abstract New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28273655/ · DOI 10.18632/aging.101202
Complete structured claim and evidence
Fisetin at 1-15 micromolar reduced the senescence-marker-positive population in etoposide-treated human IMR90 cells.
Fisetin → Senescence-marker-positive human IMR90 cells after etoposide source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
20 micromolar etoposide for 24 hours; fisetin assessed later over 48 hours.
limitations
Marker-positive cell counts do not alone identify killing versus altered marker expression.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A different induction protocol produced a different response.
primary_references
Fisetin is a senotherapeutic that extends health and lifespan. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30279143/ · DOI 10.1016/j.ebiom.2018.09.015
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 200–206
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 20 micromolar etoposide for 24 hours; fisetin assessed later over 48 hours. · source_derived_draft · unverified_draft
## fisetin-imr90-etoposide A different induction protocol produced a different response. Fisetin at 1-15 micromolar reduced the senescence-marker-positive population in etoposide-treated human IMR90 cells. Model: 20 micromolar etoposide for 24 hours; fisetin assessed later over 48 hours. Limitations: Marker-positive cell counts do not alone identify killing versus altered marker expression. Evidence access: Primary full text Fisetin is a senotherapeutic that extends health and lifespan. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30279143/ · DOI 10.1016/j.ebiom.2018.09.015
Complete structured claim and evidence
Fisetin reduced senescence markers in stressed Ercc1-deficient mouse fibroblasts without evidence of cell killing in that setting.
Fisetin → Senescence markers in Ercc1-deficient mouse embryonic fibroblasts source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Mouse fibroblast screening described in the primary study.
limitations
Do not label every marker reduction as senolysis.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A lower senescence signal can occur without killing cells.
primary_references
Fisetin is a senotherapeutic that extends health and lifespan. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30279143/ · DOI 10.1016/j.ebiom.2018.09.015
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 208–214
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse fibroblast screening described in the primary study. · source_derived_draft · unverified_draft
## fisetin-mef-marker-not-killing A lower senescence signal can occur without killing cells. Fisetin reduced senescence markers in stressed Ercc1-deficient mouse fibroblasts without evidence of cell killing in that setting. Model: Mouse fibroblast screening described in the primary study. Limitations: Do not label every marker reduction as senolysis. Evidence access: Primary full text Fisetin is a senotherapeutic that extends health and lifespan. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30279143/ · DOI 10.1016/j.ebiom.2018.09.015
Complete structured claim and evidence
Human adipose explants exposed to 20 micromolar fisetin for 48 hours showed reduced senescence markers and selected secreted inflammatory factors.
Fisetin → Human adipose-explant senescence and secretory markers source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Three biological explant replicates; washout before conditioned-medium collection.
limitations
Ex vivo exposure, not a human oral-treatment trial.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Human tissue responded outside the body.
primary_references
Fisetin is a senotherapeutic that extends health and lifespan. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30279143/ · DOI 10.1016/j.ebiom.2018.09.015
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 216–222
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Three biological explant replicates; washout before conditioned-medium collection. · source_derived_draft · unverified_draft
## fisetin-human-adipose-explant Human tissue responded outside the body. Human adipose explants exposed to 20 micromolar fisetin for 48 hours showed reduced senescence markers and selected secreted inflammatory factors. Model: Three biological explant replicates; washout before conditioned-medium collection. Limitations: Ex vivo exposure, not a human oral-treatment trial. Evidence access: Primary full text Fisetin is a senotherapeutic that extends health and lifespan. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30279143/ · DOI 10.1016/j.ebiom.2018.09.015
Complete structured claim and evidence
Late-life fisetin administration extended median and maximum lifespan in the reported wild-type mouse experiment.
Fisetin → Mouse survival during late-life fisetin intervention source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Naturally aged mice; dietary intervention.
limitations
Not established human longevity; multiple endpoints share the same study.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
An animal survival result warrants separate clinical testing.
primary_references
Fisetin is a senotherapeutic that extends health and lifespan. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30279143/ · DOI 10.1016/j.ebiom.2018.09.015
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 224–230
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Naturally aged mice; dietary intervention. · source_derived_draft · unverified_draft
## fisetin-mouse-late-life An animal survival result warrants separate clinical testing. Late-life fisetin administration extended median and maximum lifespan in the reported wild-type mouse experiment. Model: Naturally aged mice; dietary intervention. Limitations: Not established human longevity; multiple endpoints share the same study. Evidence access: Primary abstract Fisetin is a senotherapeutic that extends health and lifespan. · 2018 · https://pubmed.ncbi.nlm.nih.gov/30279143/ · DOI 10.1016/j.ebiom.2018.09.015
Complete structured claim and evidence
Intermittent oral fisetin improved grip strength and frailty in old mice and lowered selected senescence-related muscle transcripts.
Fisetin → Old-mouse grip strength and frailty during intermittent fisetin source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
One week on, two weeks off, one week on; comparisons with genetic clearance and ABT-263.
limitations
Comparable outcomes do not prove identical mechanisms.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Functional measurements accompanied molecular changes.
primary_references
Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40437670/ · DOI 10.1111/acel.70114
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 232–238
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · One week on, two weeks off, one week on; comparisons with genetic clearance and ABT-263. · source_derived_draft · unverified_draft
## fisetin-old-mouse-function Functional measurements accompanied molecular changes. Intermittent oral fisetin improved grip strength and frailty in old mice and lowered selected senescence-related muscle transcripts. Model: One week on, two weeks off, one week on; comparisons with genetic clearance and ABT-263. Limitations: Comparable outcomes do not prove identical mechanisms. Evidence access: Primary abstract Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40437670/ · DOI 10.1111/acel.70114
Complete structured claim and evidence
Fisetin did not improve the measured physical-function outcomes in young mice in the age-comparison study.
Fisetin → Young-mouse physical-function response to fisetin source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Same intermittent-supplementation study.
limitations
No detectable improvement in these endpoints is not proof of no biological activity.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Benefit was not universal across age groups.
primary_references
Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40437670/ · DOI 10.1111/acel.70114
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 240–246
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same intermittent-supplementation study. · source_derived_draft · unverified_draft
## fisetin-young-mouse-null Benefit was not universal across age groups. Fisetin did not improve the measured physical-function outcomes in young mice in the age-comparison study. Model: Same intermittent-supplementation study. Limitations: No detectable improvement in these endpoints is not proof of no biological activity. Evidence access: Primary abstract Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches. · 2025 · https://pubmed.ncbi.nlm.nih.gov/40437670/ · DOI 10.1111/acel.70114
Complete structured claim and evidence
Intermittent fisetin at 100 mg/kg/day reduced age-associated endothelial Cxcl12 expression and circulating CXCL12 in mice.
Fisetin → Mouse chemokine CXCL12 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Young/old male and female mouse aortic single-cell and plasma analyses.
limitations
Changes in expression and circulating protein are not direct CXCL12 binding.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A secreted signal connects cellular state to other vessels.
primary_references
Senolytic Treatment With Fisetin Reverses Age-Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42021544/ · DOI 10.1111/acel.70500
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 248–254
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Young/old male and female mouse aortic single-cell and plasma analyses. · source_derived_draft · unverified_draft
## fisetin-cxcl12-expression A secreted signal connects cellular state to other vessels. Intermittent fisetin at 100 mg/kg/day reduced age-associated endothelial Cxcl12 expression and circulating CXCL12 in mice. Model: Young/old male and female mouse aortic single-cell and plasma analyses. Limitations: Changes in expression and circulating protein are not direct CXCL12 binding. Evidence access: Primary abstract Senolytic Treatment With Fisetin Reverses Age-Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42021544/ · DOI 10.1111/acel.70500
Complete structured claim and evidence
Adding mouse CXCL12 back to plasma from fisetin-treated old mice reduced dilation in recipient isolated mouse arteries.
Mouse chemokine CXCL12 → Mouse artery endothelium-dependent dilation source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Recombinant CXCL12 matched old-control plasma concentration of 3210 pg/mL.
limitations
Partial mediation; other plasma components remain involved.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Replacing one secreted factor weakened the vascular improvement.
primary_references
Senolytic Treatment With Fisetin Reverses Age-Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42021544/ · DOI 10.1111/acel.70500
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 256–262
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Recombinant CXCL12 matched old-control plasma concentration of 3210 pg/mL. · source_derived_draft · unverified_draft
## fisetin-cxcl12-addback Replacing one secreted factor weakened the vascular improvement. Adding mouse CXCL12 back to plasma from fisetin-treated old mice reduced dilation in recipient isolated mouse arteries. Model: Recombinant CXCL12 matched old-control plasma concentration of 3210 pg/mL. Limitations: Partial mediation; other plasma components remain involved. Evidence access: Primary full text Senolytic Treatment With Fisetin Reverses Age-Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42021544/ · DOI 10.1111/acel.70500
Complete structured claim and evidence
Old-mouse plasma reduced NO-related bioactivity and increased mitochondrial oxidative stress in cultured human aortic endothelial cells; fisetin treatment of donor mice attenuated these effects.
Old-mouse circulating secretory milieu → Nitric-oxide bioactivity in human aortic endothelial cells exposed to mouse plasma source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse plasma applied to human endothelial culture.
limitations
Cross-species ex vivo experiment, not human oral fisetin exposure.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A plasma-transfer experiment tested effects on recipient cells.
primary_references
Senolytic Treatment With Fisetin Reverses Age-Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42021544/ · DOI 10.1111/acel.70500
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 264–270
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse plasma applied to human endothelial culture. · source_derived_draft · unverified_draft
## fisetin-cross-species-plasma A plasma-transfer experiment tested effects on recipient cells. Old-mouse plasma reduced NO-related bioactivity and increased mitochondrial oxidative stress in cultured human aortic endothelial cells; fisetin treatment of donor mice attenuated these effects. Model: Mouse plasma applied to human endothelial culture. Limitations: Cross-species ex vivo experiment, not human oral fisetin exposure. Evidence access: Primary abstract Senolytic Treatment With Fisetin Reverses Age-Related Endothelial Dysfunction Partially Mediated by SASP Factor CXCL12. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42021544/ · DOI 10.1111/acel.70500
Complete structured claim and evidence
Cell-free competition and activity assays supported fisetin binding and inhibition of mTOR in the human melanoma study.
Fisetin → Human mechanistic target of rapamycin kinase / MTOR source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human melanoma models plus cell-free kinase assays.
limitations
Docking was supplemented by biochemical assays; clinical target engagement remains unproven.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A binding assay supports a more direct target relationship.
primary_references
Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24675012/ · DOI 10.1016/j.bcp.2014.03.007
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 272–278
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human melanoma models plus cell-free kinase assays. · source_derived_draft · unverified_draft
## fisetin-mtor-binding A binding assay supports a more direct target relationship. Cell-free competition and activity assays supported fisetin binding and inhibition of mTOR in the human melanoma study. Model: Human melanoma models plus cell-free kinase assays. Limitations: Docking was supplemented by biochemical assays; clinical target engagement remains unproven. Evidence access: Primary abstract Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24675012/ · DOI 10.1016/j.bcp.2014.03.007
Complete structured claim and evidence
Cell-free competition and activity assays supported fisetin binding and inhibition of p70S6K in the human melanoma study.
Fisetin → Human p70 S6 kinase / RPS6KB1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human melanoma models plus cell-free kinase assays.
limitations
Docking was supplemented by biochemical assays; clinical target engagement remains unproven.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A binding assay supports a more direct target relationship.
primary_references
Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24675012/ · DOI 10.1016/j.bcp.2014.03.007
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 280–286
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human melanoma models plus cell-free kinase assays. · source_derived_draft · unverified_draft
## fisetin-s6k-binding A binding assay supports a more direct target relationship. Cell-free competition and activity assays supported fisetin binding and inhibition of p70S6K in the human melanoma study. Model: Human melanoma models plus cell-free kinase assays. Limitations: Docking was supplemented by biochemical assays; clinical target engagement remains unproven. Evidence access: Primary abstract Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24675012/ · DOI 10.1016/j.bcp.2014.03.007
Complete structured claim and evidence
Fisetin reduced AKT phosphorylation in human melanoma models, but showed little direct AKT affinity relative to mTOR and p70S6K.
Fisetin → AKT phosphorylation in human melanoma models source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Cell-free comparison, melanoma cultures and mouse xenografts.
limitations
Do not equate every downstream phosphorylation change with direct inhibition.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A changed signaling marker need not be a direct binding target.
primary_references
Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24675012/ · DOI 10.1016/j.bcp.2014.03.007
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 288–294
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Cell-free comparison, melanoma cultures and mouse xenografts. · source_derived_draft · unverified_draft
## fisetin-akt-indirect A changed signaling marker need not be a direct binding target. Fisetin reduced AKT phosphorylation in human melanoma models, but showed little direct AKT affinity relative to mTOR and p70S6K. Model: Cell-free comparison, melanoma cultures and mouse xenografts. Limitations: Do not equate every downstream phosphorylation change with direct inhibition. Evidence access: Primary abstract Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24675012/ · DOI 10.1016/j.bcp.2014.03.007
Complete structured claim and evidence
During mouse 3T3-L1 differentiation, fisetin reduced GLUT4 expression and glucose uptake.
Fisetin → Mouse glucose transporter 4 / Slc2a4 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Differentiating mouse adipocytes.
limitations
This is not evidence that fisetin improves glucose uptake in human muscle.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Less glucose entry reduced lipid accumulation in this model.
primary_references
Fisetin Suppresses Lipid Accumulation in Mouse Adipocytic 3T3-L1 Cells by Repressing GLUT4-Mediated Glucose Uptake through Inhibition of mTOR-C/EBPα Signaling. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25945786/ · DOI 10.1021/acs.jafc.5b00821
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Differentiating mouse adipocytes. · source_derived_draft · unverified_draft
## fisetin-adipocyte-glut4 Less glucose entry reduced lipid accumulation in this model. During mouse 3T3-L1 differentiation, fisetin reduced GLUT4 expression and glucose uptake. Model: Differentiating mouse adipocytes. Limitations: This is not evidence that fisetin improves glucose uptake in human muscle. Evidence access: Primary abstract Fisetin Suppresses Lipid Accumulation in Mouse Adipocytic 3T3-L1 Cells by Repressing GLUT4-Mediated Glucose Uptake through Inhibition of mTOR-C/EBPα Signaling. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25945786/ · DOI 10.1021/acs.jafc.5b00821
Complete structured claim and evidence
Fisetin reduced C/EBP-alpha occupancy at the GLUT4 promoter in mouse 3T3-L1 cells, alongside reduced mTOR/S6K signaling.
Fisetin → Mouse C/EBP alpha / Cebpa source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Chromatin immunoprecipitation; comparison with rapamycin.
limitations
Association and phenocopy do not resolve every direct target.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A transcriptional step links signaling to glucose transport.
primary_references
Fisetin Suppresses Lipid Accumulation in Mouse Adipocytic 3T3-L1 Cells by Repressing GLUT4-Mediated Glucose Uptake through Inhibition of mTOR-C/EBPα Signaling. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25945786/ · DOI 10.1021/acs.jafc.5b00821
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Chromatin immunoprecipitation; comparison with rapamycin. · source_derived_draft · unverified_draft
## fisetin-adipocyte-promoter A transcriptional step links signaling to glucose transport. Fisetin reduced C/EBP-alpha occupancy at the GLUT4 promoter in mouse 3T3-L1 cells, alongside reduced mTOR/S6K signaling. Model: Chromatin immunoprecipitation; comparison with rapamycin. Limitations: Association and phenocopy do not resolve every direct target. Evidence access: Primary abstract Fisetin Suppresses Lipid Accumulation in Mouse Adipocytic 3T3-L1 Cells by Repressing GLUT4-Mediated Glucose Uptake through Inhibition of mTOR-C/EBPα Signaling. · 2015 · https://pubmed.ncbi.nlm.nih.gov/25945786/ · DOI 10.1021/acs.jafc.5b00821
Complete structured claim and evidence
Fisetin inhibited glycogen-derived glucose release and gluconeogenesis in isolated rat liver at 200-300 micromolar.
Fisetin → Glucose release from isolated perfused rat liver source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Fed and fasted rat liver perfusions.
limitations
High ex vivo exposure, not a demonstrated human glucose-lowering dose.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Liver glucose output changed through more than one route.
primary_references
The actions of fisetin on glucose metabolism in the rat liver. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20084677/ · DOI 10.1002/cbf.1635
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Fed and fasted rat liver perfusions. · source_derived_draft · unverified_draft
## fisetin-rat-glucose-release Liver glucose output changed through more than one route. Fisetin inhibited glycogen-derived glucose release and gluconeogenesis in isolated rat liver at 200-300 micromolar. Model: Fed and fasted rat liver perfusions. Limitations: High ex vivo exposure, not a demonstrated human glucose-lowering dose. Evidence access: Primary abstract The actions of fisetin on glucose metabolism in the rat liver. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20084677/ · DOI 10.1002/cbf.1635
Complete structured claim and evidence
Fisetin inhibited glucose-6-phosphatase activity and increased glucose-6-phosphate content in the rat liver experiments.
Fisetin → Rat liver glucose-6-phosphatase activity source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Rat liver biochemical activity measurements.
limitations
No isoform-specific binding site was established.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
The final glucose-release step was affected.
primary_references
The actions of fisetin on glucose metabolism in the rat liver. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20084677/ · DOI 10.1002/cbf.1635
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 320–326
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat liver biochemical activity measurements. · source_derived_draft · unverified_draft
## fisetin-rat-g6pase The final glucose-release step was affected. Fisetin inhibited glucose-6-phosphatase activity and increased glucose-6-phosphate content in the rat liver experiments. Model: Rat liver biochemical activity measurements. Limitations: No isoform-specific binding site was established. Evidence access: Primary abstract The actions of fisetin on glucose metabolism in the rat liver. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20084677/ · DOI 10.1002/cbf.1635
Complete structured claim and evidence
Fisetin inhibited pyruvate carboxylation in intact rat mitochondria, but not after freeze-thaw disruption.
Fisetin → Pyruvate carboxylation in intact rat mitochondria source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Intact-mitochondrial IC50 approximately 163 micromolar.
limitations
Transport limitation is an interpretation; no direct MPC binding or biotin antagonism was shown.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Membrane access may matter more than direct carboxylase inhibition.
primary_references
The actions of fisetin on glucose metabolism in the rat liver. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20084677/ · DOI 10.1002/cbf.1635
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 328–334
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Intact-mitochondrial IC50 approximately 163 micromolar. · source_derived_draft · unverified_draft
## fisetin-rat-pyruvate-access Membrane access may matter more than direct carboxylase inhibition. Fisetin inhibited pyruvate carboxylation in intact rat mitochondria, but not after freeze-thaw disruption. Model: Intact-mitochondrial IC50 approximately 163 micromolar. Limitations: Transport limitation is an interpretation; no direct MPC binding or biotin antagonism was shown. Evidence access: Primary abstract The actions of fisetin on glucose metabolism in the rat liver. · 2010 · https://pubmed.ncbi.nlm.nih.gov/20084677/ · DOI 10.1002/cbf.1635
Complete structured claim and evidence
Fisetin reduced respiratory control and ADP/O ratios and inhibited ADP-stimulated respiration in isolated rat mitochondria.
Fisetin → Rat liver mitochondrial coupled respiration source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Alpha-ketoglutarate- or succinate-supported respiration.
limitations
Suggests effects on energy transduction; not direct structural proof of ATP-synthase binding.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Energy conversion can be impaired at experimental exposures.
primary_references
Prooxidant activity of fisetin: effects on energy metabolism in the rat liver. · 2011 · https://pubmed.ncbi.nlm.nih.gov/20957679/ · DOI 10.1002/jbt.20367
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Alpha-ketoglutarate- or succinate-supported respiration. · source_derived_draft · unverified_draft
## fisetin-rat-respiration Energy conversion can be impaired at experimental exposures. Fisetin reduced respiratory control and ADP/O ratios and inhibited ADP-stimulated respiration in isolated rat mitochondria. Model: Alpha-ketoglutarate- or succinate-supported respiration. Limitations: Suggests effects on energy transduction; not direct structural proof of ATP-synthase binding. Evidence access: Primary abstract Prooxidant activity of fisetin: effects on energy metabolism in the rat liver. · 2011 · https://pubmed.ncbi.nlm.nih.gov/20957679/ · DOI 10.1002/jbt.20367
Complete structured claim and evidence
In perfused fasted-rat liver, fisetin reduced ketogenesis and the beta-hydroxybutyrate/acetoacetate ratio.
Fisetin → Rat liver beta-hydroxybutyrate/acetoacetate ratio source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Rat liver and mitochondrial experiments.
limitations
The ketone ratio is a redox proxy, not a direct measurement of all NAD pools.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
The metabolic redox state shifted toward oxidation.
primary_references
Prooxidant activity of fisetin: effects on energy metabolism in the rat liver. · 2011 · https://pubmed.ncbi.nlm.nih.gov/20957679/ · DOI 10.1002/jbt.20367
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 344–350
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat liver and mitochondrial experiments. · source_derived_draft · unverified_draft
## fisetin-rat-redox-ketones The metabolic redox state shifted toward oxidation. In perfused fasted-rat liver, fisetin reduced ketogenesis and the beta-hydroxybutyrate/acetoacetate ratio. Model: Rat liver and mitochondrial experiments. Limitations: The ketone ratio is a redox proxy, not a direct measurement of all NAD pools. Evidence access: Primary abstract Prooxidant activity of fisetin: effects on energy metabolism in the rat liver. · 2011 · https://pubmed.ncbi.nlm.nih.gov/20957679/ · DOI 10.1002/jbt.20367
Complete structured claim and evidence
Fisetin increased proteasome activity and supported low-density rat cortical-neuron survival without trophic factors.
Fisetin → Rat cortical-neuron proteasome activity source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Serum-free rat neuron cultures.
limitations
The survival response was not dependent on glutathione or ERK in this experiment.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Protein turnover contributed to neuronal survival.
primary_references
The flavonoid fisetin promotes nerve cell survival from trophic factor withdrawal by enhancement of proteasome activity. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18396148/ · DOI 10.1016/j.abb.2008.03.023
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Serum-free rat neuron cultures. · source_derived_draft · unverified_draft
## fisetin-neuronal-proteasome Protein turnover contributed to neuronal survival. Fisetin increased proteasome activity and supported low-density rat cortical-neuron survival without trophic factors. Model: Serum-free rat neuron cultures. Limitations: The survival response was not dependent on glutathione or ERK in this experiment. Evidence access: Primary abstract The flavonoid fisetin promotes nerve cell survival from trophic factor withdrawal by enhancement of proteasome activity. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18396148/ · DOI 10.1016/j.abb.2008.03.023
Complete structured claim and evidence
Proteasome inhibitors nearly abolished fisetin-supported survival of trophic-factor-deprived rat cortical neurons.
Rat cortical-neuron proteasome activity → Rat cortical-neuron survival after trophic-factor withdrawal source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Pharmacological proteasome inhibition in rat neurons.
limitations
Not a dietary fisetin-deficiency syndrome.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Blocking downstream machinery prevented the response.
primary_references
The flavonoid fisetin promotes nerve cell survival from trophic factor withdrawal by enhancement of proteasome activity. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18396148/ · DOI 10.1016/j.abb.2008.03.023
trigger_kind
machinery_impairment Imported condition classification; unverified.
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 360–366
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Pharmacological proteasome inhibition in rat neurons. · source_derived_draft · unverified_draft
## fisetin-proteasome-block Blocking downstream machinery prevented the response. Proteasome inhibitors nearly abolished fisetin-supported survival of trophic-factor-deprived rat cortical neurons. Model: Pharmacological proteasome inhibition in rat neurons. Limitations: Not a dietary fisetin-deficiency syndrome. Evidence access: Primary abstract The flavonoid fisetin promotes nerve cell survival from trophic factor withdrawal by enhancement of proteasome activity. · 2008 · https://pubmed.ncbi.nlm.nih.gov/18396148/ · DOI 10.1016/j.abb.2008.03.023
Complete structured claim and evidence
Fisetin increased ROS and AMPK-associated signaling in human U266 myeloma cells undergoing apoptosis.
Fisetin → Reactive-oxygen generation in human U266 cells source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human tumor cell culture.
limitations
Different from protection of nonmalignant cells; not an established cancer therapy.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A pro-oxidant response can contribute to cell killing.
primary_references
Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22261340/ · DOI 10.1016/j.canlet.2012.01.008
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 368–374
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human tumor cell culture. · source_derived_draft · unverified_draft
## fisetin-u266-ros A pro-oxidant response can contribute to cell killing. Fisetin increased ROS and AMPK-associated signaling in human U266 myeloma cells undergoing apoptosis. Model: Human tumor cell culture. Limitations: Different from protection of nonmalignant cells; not an established cancer therapy. Evidence access: Primary abstract Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22261340/ · DOI 10.1016/j.canlet.2012.01.008
Complete structured claim and evidence
N-acetylcysteine blocked fisetin-induced apoptosis in human U266 cells.
N-Acetyl-L-cysteine → Fisetin-associated apoptosis in human U266 myeloma cells source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Tumor-cell cotreatment experiment.
limitations
Does not establish a clinical fisetin-NAC interaction or show whether oral exposures reproduce it.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
An antioxidant intervention weakened the cell-killing response.
primary_references
Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22261340/ · DOI 10.1016/j.canlet.2012.01.008
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 376–382
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Tumor-cell cotreatment experiment. · source_derived_draft · unverified_draft
## fisetin-u266-nac-rescue An antioxidant intervention weakened the cell-killing response. N-acetylcysteine blocked fisetin-induced apoptosis in human U266 cells. Model: Tumor-cell cotreatment experiment. Limitations: Does not establish a clinical fisetin-NAC interaction or show whether oral exposures reproduce it. Evidence access: Primary abstract Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22261340/ · DOI 10.1016/j.canlet.2012.01.008
Complete structured claim and evidence
Compound C blocked fisetin-induced apoptosis in human U266 cells.
Compound C / dorsomorphin → Fisetin-associated apoptosis in human U266 myeloma cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Pharmacological AMPK-pathway perturbation.
limitations
Compound C has off-target activity; this is not equivalent to AMPK-specific genetic proof.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A kinase-pathway inhibitor also weakened the response.
primary_references
Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22261340/ · DOI 10.1016/j.canlet.2012.01.008
trigger_kind
machinery_impairment Imported condition classification; unverified.
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 384–390
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Pharmacological AMPK-pathway perturbation. · source_derived_draft · unverified_draft
## fisetin-u266-ampk-inhibitor A kinase-pathway inhibitor also weakened the response. Compound C blocked fisetin-induced apoptosis in human U266 cells. Model: Pharmacological AMPK-pathway perturbation. Limitations: Compound C has off-target activity; this is not equivalent to AMPK-specific genetic proof. Evidence access: Primary abstract Activation of reactive oxygen species/AMP activated protein kinase signaling mediates fisetin-induced apoptosis in multiple myeloma U266 cells. · 2012 · https://pubmed.ncbi.nlm.nih.gov/22261340/ · DOI 10.1016/j.canlet.2012.01.008
Complete structured claim and evidence
Fisetin restored Cdkn1b expression in high-glucose-exposed mouse podocytes and diabetic mouse kidney.
Fisetin → Mouse p27 / Cdkn1b source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Immortalized mouse podocytes and streptozotocin diabetic mice.
limitations
Docking suggests a possible interaction but does not demonstrate direct binding.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A cell-cycle regulator was linked to protection.
primary_references
Fisetin Attenuates Diabetic Nephropathy-Induced Podocyte Injury by Inhibiting NLRP3 Inflammasome. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35126159/ · DOI 10.3389/fphar.2022.783706
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Immortalized mouse podocytes and streptozotocin diabetic mice. · source_derived_draft · unverified_draft
## fisetin-podocyte-p27 A cell-cycle regulator was linked to protection. Fisetin restored Cdkn1b expression in high-glucose-exposed mouse podocytes and diabetic mouse kidney. Model: Immortalized mouse podocytes and streptozotocin diabetic mice. Limitations: Docking suggests a possible interaction but does not demonstrate direct binding. Evidence access: Primary full text Fisetin Attenuates Diabetic Nephropathy-Induced Podocyte Injury by Inhibiting NLRP3 Inflammasome. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35126159/ · DOI 10.3389/fphar.2022.783706
Complete structured claim and evidence
Fisetin reduced p70S6K phosphorylation, increased autophagosome formation and suppressed inflammasome readouts in mouse podocyte models.
Fisetin → Mouse podocyte NLRP3 inflammasome activation source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Mouse podocytes and diabetic kidney study.
limitations
Autophagosome number alone does not establish complete autophagic flux.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Protein recycling and inflammatory signaling changed together.
primary_references
Fisetin Attenuates Diabetic Nephropathy-Induced Podocyte Injury by Inhibiting NLRP3 Inflammasome. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35126159/ · DOI 10.3389/fphar.2022.783706
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse podocytes and diabetic kidney study. · source_derived_draft · unverified_draft
## fisetin-podocyte-autophagy Protein recycling and inflammatory signaling changed together. Fisetin reduced p70S6K phosphorylation, increased autophagosome formation and suppressed inflammasome readouts in mouse podocyte models. Model: Mouse podocytes and diabetic kidney study. Limitations: Autophagosome number alone does not establish complete autophagic flux. Evidence access: Primary abstract Fisetin Attenuates Diabetic Nephropathy-Induced Podocyte Injury by Inhibiting NLRP3 Inflammasome. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35126159/ · DOI 10.3389/fphar.2022.783706
Complete structured claim and evidence
Cdkn1b interference reduced fisetin protection against high-glucose injury in mouse podocytes.
Mouse p27 / Cdkn1b → High-glucose injury in mouse podocytes source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
Mouse podocyte gene-interference experiment.
limitations
A pathway dependency, not evidence of a nutritional deficiency.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Disrupting the regulator weakened protection.
primary_references
Fisetin Attenuates Diabetic Nephropathy-Induced Podocyte Injury by Inhibiting NLRP3 Inflammasome. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35126159/ · DOI 10.3389/fphar.2022.783706
trigger_kind
machinery_impairment Imported condition classification; unverified.
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 408–414
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Mouse podocyte gene-interference experiment. · source_derived_draft · unverified_draft
## fisetin-podocyte-p27-loss Disrupting the regulator weakened protection. Cdkn1b interference reduced fisetin protection against high-glucose injury in mouse podocytes. Model: Mouse podocyte gene-interference experiment. Limitations: A pathway dependency, not evidence of a nutritional deficiency. Evidence access: Primary full text Fisetin Attenuates Diabetic Nephropathy-Induced Podocyte Injury by Inhibiting NLRP3 Inflammasome. · 2022 · https://pubmed.ncbi.nlm.nih.gov/35126159/ · DOI 10.3389/fphar.2022.783706
Complete structured claim and evidence
Fisetin restored GPX4 protein and glutathione while reducing lipid-oxidation markers in doxorubicin-exposed rat hearts and H9c2 cells.
Fisetin → Rat glutathione peroxidase 4 / Gpx4 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary full text
experimental_model
Rat model; H9c2 assays used 40 micromolar fisetin with 1 micromolar doxorubicin for 24 hours.
limitations
Does not establish selenium replacement or preservation of anticancer efficacy.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A selenium-containing defense pathway accompanied protection.
primary_references
Fisetin Attenuates Doxorubicin-Induced Cardiomyopathy In Vivo and In Vitro by Inhibiting Ferroptosis Through SIRT1/Nrf2 Signaling Pathway Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/35273493/ · DOI 10.3389/fphar.2021.808480
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat model; H9c2 assays used 40 micromolar fisetin with 1 micromolar doxorubicin for 24 hours. · source_derived_draft · unverified_draft
## fisetin-cardiac-gpx4 A selenium-containing defense pathway accompanied protection. Fisetin restored GPX4 protein and glutathione while reducing lipid-oxidation markers in doxorubicin-exposed rat hearts and H9c2 cells. Model: Rat model; H9c2 assays used 40 micromolar fisetin with 1 micromolar doxorubicin for 24 hours. Limitations: Does not establish selenium replacement or preservation of anticancer efficacy. Evidence access: Primary full text Fisetin Attenuates Doxorubicin-Induced Cardiomyopathy In Vivo and In Vitro by Inhibiting Ferroptosis Through SIRT1/Nrf2 Signaling Pathway Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/35273493/ · DOI 10.3389/fphar.2021.808480
Complete structured claim and evidence
Fisetin increased SIRT1 and nuclear Nrf2-associated signaling in the rat cardiac study, with HO-1 and ferritin-heavy-chain expression changes.
Fisetin → Rat Nrf2 / Nfe2l2 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Rat hearts and rat H9c2 cells.
limitations
Expression is not direct enzyme activation or proof of every transcriptional step.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Iron handling and antioxidant signaling were linked.
primary_references
Fisetin Attenuates Doxorubicin-Induced Cardiomyopathy In Vivo and In Vitro by Inhibiting Ferroptosis Through SIRT1/Nrf2 Signaling Pathway Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/35273493/ · DOI 10.3389/fphar.2021.808480
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AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat hearts and rat H9c2 cells. · source_derived_draft · unverified_draft
## fisetin-cardiac-nrf2 Iron handling and antioxidant signaling were linked. Fisetin increased SIRT1 and nuclear Nrf2-associated signaling in the rat cardiac study, with HO-1 and ferritin-heavy-chain expression changes. Model: Rat hearts and rat H9c2 cells. Limitations: Expression is not direct enzyme activation or proof of every transcriptional step. Evidence access: Primary abstract Fisetin Attenuates Doxorubicin-Induced Cardiomyopathy In Vivo and In Vitro by Inhibiting Ferroptosis Through SIRT1/Nrf2 Signaling Pathway Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/35273493/ · DOI 10.3389/fphar.2021.808480
Complete structured claim and evidence
SIRT1 inhibition attenuated fisetin protection in doxorubicin-exposed H9c2 cells and reduced the associated GSH/GPX4 response.
Rat sirtuin 1 / Sirt1 → Fisetin-associated protection in rat H9c2 cells source_derived_draftungraded
Experimental context and source evidence
availability_state
machinery_impairment Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Rat cardiac-cell pharmacological inhibition.
limitations
Not proof that niacin or NAD supplements enhance fisetin.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
An intact regulatory pathway was required for the full response.
primary_references
Fisetin Attenuates Doxorubicin-Induced Cardiomyopathy In Vivo and In Vitro by Inhibiting Ferroptosis Through SIRT1/Nrf2 Signaling Pathway Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/35273493/ · DOI 10.3389/fphar.2021.808480
trigger_kind
machinery_impairment Imported condition classification; unverified.
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 432–438
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Rat cardiac-cell pharmacological inhibition. · source_derived_draft · unverified_draft
## fisetin-cardiac-sirt1-block An intact regulatory pathway was required for the full response. SIRT1 inhibition attenuated fisetin protection in doxorubicin-exposed H9c2 cells and reduced the associated GSH/GPX4 response. Model: Rat cardiac-cell pharmacological inhibition. Limitations: Not proof that niacin or NAD supplements enhance fisetin. Evidence access: Primary abstract Fisetin Attenuates Doxorubicin-Induced Cardiomyopathy In Vivo and In Vitro by Inhibiting Ferroptosis Through SIRT1/Nrf2 Signaling Pathway Activation. · 2021 · https://pubmed.ncbi.nlm.nih.gov/35273493/ · DOI 10.3389/fphar.2021.808480
Complete structured claim and evidence
In high-glucose-treated human THP-1 cells, 500 nM fisetin plus 500 nM or 1 micromolar luteolin suppressed inflammatory output.
Fisetin → Luteolin / 3′,4′,5,7-tetrahydroxyflavone source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
20 mM glucose for 48 hours with osmotic and normoglycemic controls.
limitations
Combination activity is not demonstrated clinical synergy; assess interaction statistics before claiming more-than-additive benefit.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Two compounds were actually tested together.
primary_references
Combination Treatments with Luteolin and Fisetin Enhance Anti-Inflammatory Effects in High Glucose-Treated THP-1 Cells Through Histone Acetyltransferase/Histone Deacetylase Regulation. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28650731/ · DOI 10.1089/jmf.2017.3968
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 440–446
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 20 mM glucose for 48 hours with osmotic and normoglycemic controls. · source_derived_draft · unverified_draft
## fisetin-luteolin-combination Two compounds were actually tested together. In high-glucose-treated human THP-1 cells, 500 nM fisetin plus 500 nM or 1 micromolar luteolin suppressed inflammatory output. Model: 20 mM glucose for 48 hours with osmotic and normoglycemic controls. Limitations: Combination activity is not demonstrated clinical synergy; assess interaction statistics before claiming more-than-additive benefit. Evidence access: Primary abstract Combination Treatments with Luteolin and Fisetin Enhance Anti-Inflammatory Effects in High Glucose-Treated THP-1 Cells Through Histone Acetyltransferase/Histone Deacetylase Regulation. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28650731/ · DOI 10.1089/jmf.2017.3968
Complete structured claim and evidence
Fisetin, luteolin and combination treatments reduced histone-acetyltransferase activity in high-glucose-treated human THP-1 cells.
Fisetin → Histone acetyltransferase activity in human THP-1 cells source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human monocytic cell culture.
limitations
No unique HAT isoform or direct binding site was resolved in the abstract.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Chromatin-regulating activity accompanied the inflammatory response.
primary_references
Combination Treatments with Luteolin and Fisetin Enhance Anti-Inflammatory Effects in High Glucose-Treated THP-1 Cells Through Histone Acetyltransferase/Histone Deacetylase Regulation. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28650731/ · DOI 10.1089/jmf.2017.3968
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 448–454
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human monocytic cell culture. · source_derived_draft · unverified_draft
## fisetin-histone-enzyme-response Chromatin-regulating activity accompanied the inflammatory response. Fisetin, luteolin and combination treatments reduced histone-acetyltransferase activity in high-glucose-treated human THP-1 cells. Model: Human monocytic cell culture. Limitations: No unique HAT isoform or direct binding site was resolved in the abstract. Evidence access: Primary abstract Combination Treatments with Luteolin and Fisetin Enhance Anti-Inflammatory Effects in High Glucose-Treated THP-1 Cells Through Histone Acetyltransferase/Histone Deacetylase Regulation. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28650731/ · DOI 10.1089/jmf.2017.3968
Complete structured claim and evidence
The THP-1 treatments increased SIRT1 and FOXO3a expression while suppressing high-glucose inflammatory responses.
Fisetin → SIRT1 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Fisetin, luteolin and combination conditions in human cells.
limitations
Expression is not proven direct SIRT1 activation or greater NAD availability.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
This branch connects to NAD-dependent cell regulation.
primary_references
Combination Treatments with Luteolin and Fisetin Enhance Anti-Inflammatory Effects in High Glucose-Treated THP-1 Cells Through Histone Acetyltransferase/Histone Deacetylase Regulation. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28650731/ · DOI 10.1089/jmf.2017.3968
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 456–462
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Fisetin, luteolin and combination conditions in human cells. · source_derived_draft · unverified_draft
## fisetin-sirt1-foxo-response This branch connects to NAD-dependent cell regulation. The THP-1 treatments increased SIRT1 and FOXO3a expression while suppressing high-glucose inflammatory responses. Model: Fisetin, luteolin and combination conditions in human cells. Limitations: Expression is not proven direct SIRT1 activation or greater NAD availability. Evidence access: Primary abstract Combination Treatments with Luteolin and Fisetin Enhance Anti-Inflammatory Effects in High Glucose-Treated THP-1 Cells Through Histone Acetyltransferase/Histone Deacetylase Regulation. · 2017 · https://pubmed.ncbi.nlm.nih.gov/28650731/ · DOI 10.1089/jmf.2017.3968
Complete structured claim and evidence
Fisetin reversibly and noncompetitively inhibited CYP2C8-mediated paclitaxel hydroxylation in human liver microsomes, with reported Ki 4.1 micromolar.
Fisetin → Human cytochrome P450 2C8 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Pooled human liver microsomes; preincubation and kinetic comparisons.
limitations
In vitro hazard signal; no measured clinical drug-exposure change or dosing adjustment follows.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
The parent and metabolite can affect the same drug-metabolizing enzyme.
primary_references
Selective inhibition of CYP2C8 by fisetin and its methylated metabolite, geraldol, in human liver microsomes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29454704/ · DOI 10.1016/j.dmpk.2017.12.006
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 464–470
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Pooled human liver microsomes; preincubation and kinetic comparisons. · source_derived_draft · unverified_draft
## fisetin-cyp2c8-parent The parent and metabolite can affect the same drug-metabolizing enzyme. Fisetin reversibly and noncompetitively inhibited CYP2C8-mediated paclitaxel hydroxylation in human liver microsomes, with reported Ki 4.1 micromolar. Model: Pooled human liver microsomes; preincubation and kinetic comparisons. Limitations: In vitro hazard signal; no measured clinical drug-exposure change or dosing adjustment follows. Evidence access: Primary abstract Selective inhibition of CYP2C8 by fisetin and its methylated metabolite, geraldol, in human liver microsomes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29454704/ · DOI 10.1016/j.dmpk.2017.12.006
Complete structured claim and evidence
Geraldol reversibly and noncompetitively inhibited CYP2C8-mediated paclitaxel hydroxylation in human liver microsomes, with reported Ki 11.5 micromolar.
Geraldol / 3-prime-O-methylfisetin → Human cytochrome P450 2C8 source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Pooled human liver microsomes; preincubation and kinetic comparisons.
limitations
In vitro hazard signal; no measured clinical drug-exposure change or dosing adjustment follows.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
The parent and metabolite can affect the same drug-metabolizing enzyme.
primary_references
Selective inhibition of CYP2C8 by fisetin and its methylated metabolite, geraldol, in human liver microsomes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29454704/ · DOI 10.1016/j.dmpk.2017.12.006
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 472–478
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Pooled human liver microsomes; preincubation and kinetic comparisons. · source_derived_draft · unverified_draft
## fisetin-cyp2c8-metabolite The parent and metabolite can affect the same drug-metabolizing enzyme. Geraldol reversibly and noncompetitively inhibited CYP2C8-mediated paclitaxel hydroxylation in human liver microsomes, with reported Ki 11.5 micromolar. Model: Pooled human liver microsomes; preincubation and kinetic comparisons. Limitations: In vitro hazard signal; no measured clinical drug-exposure change or dosing adjustment follows. Evidence access: Primary abstract Selective inhibition of CYP2C8 by fisetin and its methylated metabolite, geraldol, in human liver microsomes. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29454704/ · DOI 10.1016/j.dmpk.2017.12.006
Complete structured claim and evidence
Fisetin inhibited human topoisomerase II-alpha in an isolated enzyme assay.
Fisetin → Human DNA topoisomerase II alpha / TOP2A source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Biochemical confirmation accompanying human-cell genotoxicity testing.
limitations
Does not quantify risk from ordinary dietary intake.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
DNA-handling machinery is another experimental target.
primary_references
Chromosomal malsegregation and micronucleus induction in vitro by the DNA topoisomerase II inhibitor fisetin. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15781213/ · DOI 10.1016/j.mrgentox.2005.01.002
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 480–486
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Biochemical confirmation accompanying human-cell genotoxicity testing. · source_derived_draft · unverified_draft
## fisetin-topoisomerase DNA-handling machinery is another experimental target. Fisetin inhibited human topoisomerase II-alpha in an isolated enzyme assay. Model: Biochemical confirmation accompanying human-cell genotoxicity testing. Limitations: Does not quantify risk from ordinary dietary intake. Evidence access: Primary abstract Chromosomal malsegregation and micronucleus induction in vitro by the DNA topoisomerase II inhibitor fisetin. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15781213/ · DOI 10.1016/j.mrgentox.2005.01.002
Complete structured claim and evidence
Fisetin increased chromosome missegregation and kinetochore-positive micronuclei in TK6 and HL60 cells; breakage-related micronuclei appeared at higher tested concentrations.
Fisetin → Chromosome missegregation in human TK6 and HL60 cultures source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Human cultured-cell cytokinesis-block/CREST assays.
limitations
Exposure-specific hazard characterization, not demonstrated human cancer risk.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Cell-culture toxicity included chromosome loss and breakage.
primary_references
Chromosomal malsegregation and micronucleus induction in vitro by the DNA topoisomerase II inhibitor fisetin. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15781213/ · DOI 10.1016/j.mrgentox.2005.01.002
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 488–494
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human cultured-cell cytokinesis-block/CREST assays. · source_derived_draft · unverified_draft
## fisetin-chromosome-segregation Cell-culture toxicity included chromosome loss and breakage. Fisetin increased chromosome missegregation and kinetochore-positive micronuclei in TK6 and HL60 cells; breakage-related micronuclei appeared at higher tested concentrations. Model: Human cultured-cell cytokinesis-block/CREST assays. Limitations: Exposure-specific hazard characterization, not demonstrated human cancer risk. Evidence access: Primary abstract Chromosomal malsegregation and micronucleus induction in vitro by the DNA topoisomerase II inhibitor fisetin. · 2005 · https://pubmed.ncbi.nlm.nih.gov/15781213/ · DOI 10.1016/j.mrgentox.2005.01.002
Complete structured claim and evidence
Fisetin produced numerical chromosome abnormalities in human TK6 cells, with hyperdiploidy/polyploidy most evident after recovery from a cell-cycle delay.
Fisetin → Polyploidy and hyperdiploidy in fisetin-treated human TK6 cells source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Comparison with two Aurora kinase inhibitors.
limitations
Phenotypic similarity does not establish exclusive Aurora B mediation.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Timing affected when chromosome abnormalities were detected.
primary_references
A comparative study of the aneugenic and polyploidy-inducing effects of fisetin and two model Aurora kinase inhibitors. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24680981/ · DOI 10.1016/j.mrgentox.2014.03.004
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 496–502
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Comparison with two Aurora kinase inhibitors. · source_derived_draft · unverified_draft
## fisetin-polyploidy Timing affected when chromosome abnormalities were detected. Fisetin produced numerical chromosome abnormalities in human TK6 cells, with hyperdiploidy/polyploidy most evident after recovery from a cell-cycle delay. Model: Comparison with two Aurora kinase inhibitors. Limitations: Phenotypic similarity does not establish exclusive Aurora B mediation. Evidence access: Primary abstract A comparative study of the aneugenic and polyploidy-inducing effects of fisetin and two model Aurora kinase inhibitors. · 2014 · https://pubmed.ncbi.nlm.nih.gov/24680981/ · DOI 10.1016/j.mrgentox.2014.03.004
Complete structured claim and evidence
In 37 colorectal-cancer patients receiving chemotherapy, 100 mg/day fisetin for seven weeks lowered plasma IL-8 relative to placebo.
Fisetin → Human interleukin-8 / CXCL8 source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Randomized double-blind trial; 18 fisetin and 19 placebo.
limitations
No tumor-response or survival benefit demonstrated; plasma concentration is not direct cytokine binding.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A small trial measured an inflammatory marker response.
primary_references
Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29541713/ · DOI 10.1039/c7fo01898c
trigger_kind
biomarker_context Imported condition classification; unverified.
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 504–510
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Randomized double-blind trial; 18 fisetin and 19 placebo. · source_derived_draft · unverified_draft
## fisetin-crc-il8 A small trial measured an inflammatory marker response. In 37 colorectal-cancer patients receiving chemotherapy, 100 mg/day fisetin for seven weeks lowered plasma IL-8 relative to placebo. Model: Randomized double-blind trial; 18 fisetin and 19 placebo. Limitations: No tumor-response or survival benefit demonstrated; plasma concentration is not direct cytokine binding. Evidence access: Primary abstract Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29541713/ · DOI 10.1039/c7fo01898c
Complete structured claim and evidence
Only IL-8 showed a significant between-group change; within-group decreases in hs-CRP and MMP-7 did not establish placebo-controlled benefits.
Fisetin → Other plasma markers in the fisetin colorectal-cancer trial source_derived_draftungraded
Experimental context and source evidence
evidence_access
Primary abstract
experimental_model
Same 37-person trial.
limitations
Retains the negative comparison rather than promoting all measured trends.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
Within-group improvement is not the same as a treatment effect.
primary_references
Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29541713/ · DOI 10.1039/c7fo01898c
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 512–518
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Same 37-person trial. · source_derived_draft · unverified_draft
## fisetin-crc-other-markers-null Within-group improvement is not the same as a treatment effect. Only IL-8 showed a significant between-group change; within-group decreases in hs-CRP and MMP-7 did not establish placebo-controlled benefits. Model: Same 37-person trial. Limitations: Retains the negative comparison rather than promoting all measured trends. Evidence access: Primary abstract Effect of fisetin supplementation on inflammatory factors and matrix metalloproteinase enzymes in colorectal cancer patients. · 2018 · https://pubmed.ncbi.nlm.nih.gov/29541713/ · DOI 10.1039/c7fo01898c
Complete structured claim and evidence
The 12-week four-arm trial reported the largest asprosin and MCP-1 reductions in men receiving exercise plus 200 mg/day fisetin.
Fisetin plus interval resistance/aerobic exercise → Asprosin and MCP-1 in the fisetin/exercise trial source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
60 randomized; intention-to-treat analysis, 44 per-protocol; IRCT20120129008863N14.
limitations
Largest change alone does not establish synergy. Abstract BMI inequality is inconsistent with full-text BMI >30 eligibility.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
A combined intervention changed metabolic-inflammatory markers.
primary_references
The Effects of Interval Resistance-Aerobic Training and Fisetin Supplementation on Asprosin and Selected Adipokines in Obese Men: A Double-Blind Randomized Control Trial. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41683255/ · DOI 10.3390/nu18030433
trigger_kind
biomarker_context Imported condition classification; unverified.
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 520–526
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 60 randomized; intention-to-treat analysis, 44 per-protocol; IRCT20120129008863N14. · source_derived_draft · unverified_draft
## fisetin-obesity-adipokines A combined intervention changed metabolic-inflammatory markers. The 12-week four-arm trial reported the largest asprosin and MCP-1 reductions in men receiving exercise plus 200 mg/day fisetin. Model: 60 randomized; intention-to-treat analysis, 44 per-protocol; IRCT20120129008863N14. Limitations: Largest change alone does not establish synergy. Abstract BMI inequality is inconsistent with full-text BMI >30 eligibility. Evidence access: Primary full text The Effects of Interval Resistance-Aerobic Training and Fisetin Supplementation on Asprosin and Selected Adipokines in Obese Men: A Double-Blind Randomized Control Trial. · 2026 · https://pubmed.ncbi.nlm.nih.gov/41683255/ · DOI 10.3390/nu18030433
Complete structured claim and evidence
The related exercise/fisetin report found maresin-1 increases in the training-placebo and training-fisetin arms.
Fisetin plus interval resistance/aerobic exercise → Plasma maresin-1 in the fisetin/exercise trial source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary full text
experimental_model
44 completers; same IRCT20120129008863N14 registration as the adipokine paper.
limitations
Linked report, not independent replication; circulating maresin does not demonstrate its biosynthetic mechanism.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
The exercise response cannot be assigned entirely to fisetin.
primary_references
12‑weeks fisetin supplementation and interval resistance with aerobic training: changes in Maresin‑1 and inflammatory markers in men with obesity: a randomized controlled trial. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42218768/ · DOI 10.1080/15502783.2026.2679718
trigger_kind
biomarker_context Imported condition classification; unverified.
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 528–534
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · 44 completers; same IRCT20120129008863N14 registration as the adipokine paper. · source_derived_draft · unverified_draft
## fisetin-obesity-maresin The exercise response cannot be assigned entirely to fisetin. The related exercise/fisetin report found maresin-1 increases in the training-placebo and training-fisetin arms. Model: 44 completers; same IRCT20120129008863N14 registration as the adipokine paper. Limitations: Linked report, not independent replication; circulating maresin does not demonstrate its biosynthetic mechanism. Evidence access: Primary full text 12‑weeks fisetin supplementation and interval resistance with aerobic training: changes in Maresin‑1 and inflammatory markers in men with obesity: a randomized controlled trial. · 2026 · https://pubmed.ncbi.nlm.nih.gov/42218768/ · DOI 10.1080/15502783.2026.2679718
Complete structured claim and evidence
A 19-person DQF pilot reported nonsignificant increases in selected epigenetic-age measures after six months, unlike increases in an earlier DQ cohort.
Dasatinib-quercetin-fisetin combination → Human DNA-methylation-clock response during DQF pilot source_derived_draftungraded
Experimental context and source evidence
availability_state
biomarker_context Imported condition classification; unverified.
evidence_access
Primary abstract
experimental_model
Sequential cohorts, ten overlapping participants; combined drug/flavonoid exposure.
limitations
Not a randomized fisetin-only comparison; changing immune-cell proportions can affect clock interpretation.
nutrient_topic
Fisetin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Fisetin
plain_language
This pilot did not isolate a fisetin effect or show age reversal.
primary_references
Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38393697/ · DOI 10.18632/aging.205581
trigger_kind
biomarker_context Imported condition classification; unverified.
Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 536–542
AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Sequential cohorts, ten overlapping participants; combined drug/flavonoid exposure. · source_derived_draft · unverified_draft
## fisetin-epigenetic-clock-pilot This pilot did not isolate a fisetin effect or show age reversal. A 19-person DQF pilot reported nonsignificant increases in selected epigenetic-age measures after six months, unlike increases in an earlier DQ cohort. Model: Sequential cohorts, ten overlapping participants; combined drug/flavonoid exposure. Limitations: Not a randomized fisetin-only comparison; changing immune-cell proportions can affect clock interpretation. Evidence access: Primary abstract Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38393697/ · DOI 10.18632/aging.205581
Complete structured claim and evidence
Glutamate-cysteine ligase joins glutamate and cysteine to form gamma-glutamylcysteine in the first glutathione-synthesis step.
Human glutamate-cysteine ligase catalytic subunit / GCLC → Gamma-glutamylcysteine source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/sulforaphane-research/30581542.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77cf6674cf9b9bc140a228588a53c937966fd3a67397c1c4970221c5cc58a0b1", "start_char": 762, "end_char": 1092, "text_sha256": "927fa13b085700c20b578ecabc7c8c17a66ea4600b90809e3061d12bcaea3849"}
experimental_model
Human enzyme mutagenesis, kinetics and molecular dynamics
exposure
S-loop variants; established biosynthetic reactions described in the introduction
limitations
Reaction descriptions are background chemistry in a primary enzyme paper, not evidence that sulforaphane corrects inherited GSS deficiency.
nutrient_topic
Sulforaphane research collection; topical membership is not evidence of a direct dietary effect. · Sulforaphane / SFN, stereochemistry specified per study
organism
Human GSS
plain_language
The induced machinery still needs its amino-acid building blocks.
primary_references
[sulforaphane-p30581542] Genetic Mutations in the S-loop of Human Glutathione Synthetase: Links Between Substrate Binding, Active Site Structure and Allostery. (2019). https://pubmed.ncbi.nlm.nih.gov/30581542/ DOI: 10.1016/j.csbj.2018.11.008
tissue_or_cell_type
Glutathione synthesis and substrate binding
Sulforaphane: formation, electrophile sensing and nutrient connections (2026-09-17) · lines 840–851
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human enzyme mutagenesis, kinetics and molecular dynamics · source_derived_draft · unverified_draft
### sulforaphane-gcl-first-step Glutamate-cysteine ligase joins glutamate and cysteine to form gamma-glutamylcysteine in the first glutathione-synthesis step. Condition category: normal nutrient_topic: Sulforaphane research collection; topical membership is not evidence of a direct dietary effect. plain_language: The induced machinery still needs its amino-acid building blocks. organism: Human GSS tissue_or_cell_type: Glutathione synthesis and substrate binding experimental_model: Human enzyme mutagenesis, kinetics and molecular dynamics limitations: Reaction descriptions are background chemistry in a primary enzyme paper, not evidence that sulforaphane corrects inherited GSS deficiency. exposure: S-loop variants; established biosynthetic reactions described in the introduction evidence_span: {"source_cache": "artifacts/sulforaphane-research/30581542.fulltext.txt", "locator": "Primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "77cf6674cf9b9bc140a228588a53c937966fd3a67397c1c4970221c5cc58a0b1", "start_char": 762, "end_char": 1092, "text_sha256": "927fa13b085700c20b578ecabc7c8c17a66ea4600b90809e3061d12bcaea3849"} [sulforaphane-p30581542] Genetic Mutations in the S-loop of Human Glutathione Synthetase: Links Between Substrate Binding, Active Site Structure and Allostery. (2019). https://pubmed.ncbi.nlm.nih.gov/30581542/ DOI: 10.1016/j.csbj.2018.11.008
Complete structured claim and evidence
GSR reduces one glutathione-disulfide molecule to two reduced glutathione molecules using the NADPH/FAD catalytic relay.
Glutathione reductase / GSR → GSSG source_derived_draftungraded
Experimental context and source evidence
cross_nutrient
B2-FAD supports GSH recycling; selenium-dependent GPX use of GSH is a separate reaction.
evidence_location
Results: NADPH binding; Fig 1 consensus cycle; GSH/GSSG complexes
experimental_model
Purified human glutathione reductase crystals with natural substrates, 0.95-1.1-A resolution, chemically reduced controls.
exposure
Purified-enzyme assay
limitations
GSR is not glutathione peroxidase; this record does not show that B2 improves selenium repletion.
nutrient_topic
Riboflavin research collection; topical membership is not evidence of a direct dietary effect. · Riboflavin (vitamin B2)
organism
Homo sapiens
plain_language
This enzyme recycles glutathione after oxidation.
primary_references
[berkholz2008] Catalytic cycle of human glutathione reductase near 1 A resolution. (2008). https://pubmed.ncbi.nlm.nih.gov/18638483/ DOI: 10.1016/j.jmb.2008.06.083
tissue_or_cell_type
Purified human GSR
Riboflavin: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 1332–1344
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human glutathione reductase crystals with natural substrates, 0.95-1.1-A resolution, chemically reduced controls. · source_derived_draft · unverified_draft
### b2-gsr-gssg-to-gsh GSR reduces one glutathione-disulfide molecule to two reduced glutathione molecules using the NADPH/FAD catalytic relay. Condition category: normal nutrient_topic: Riboflavin research collection; topical membership is not evidence of a direct dietary effect. plain_language: This enzyme recycles glutathione after oxidation. organism: Homo sapiens tissue_or_cell_type: Purified human GSR experimental_model: Purified human glutathione reductase crystals with natural substrates, 0.95-1.1-A resolution, chemically reduced controls. limitations: GSR is not glutathione peroxidase; this record does not show that B2 improves selenium repletion. exposure: Purified-enzyme assay cross_nutrient: B2-FAD supports GSH recycling; selenium-dependent GPX use of GSH is a separate reaction. evidence_location: Results: NADPH binding; Fig 1 consensus cycle; GSH/GSSG complexes [berkholz2008] Catalytic cycle of human glutathione reductase near 1 A resolution. (2008). https://pubmed.ncbi.nlm.nih.gov/18638483/ DOI: 10.1016/j.jmb.2008.06.083
Complete structured claim and evidence
Human soluble COMT structures resolve bound SAM.
Human catechol O-methyltransferase / COMT → S-Adenosyl-L-methionine source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/chlorogenic_acid-research/18486144.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9cafbfc9353f49fab9919bc64608f21f445ace4b190771e44088a5a746e5a6e3", "start_char": 0, "end_char": 1961, "text_sha256": "9cafbfc9353f49fab9919bc64608f21f445ace4b190771e44088a5a746e5a6e3"}
experimental_model
Human soluble COMT crystallography and deposited structure 3BWM
exposure
SAM and 3,5-dinitrocatechol-bound crystals; deposited Mg ion
limitations
Structural cofactor connection, not a CGA-magnesium supplementation trial. Human and rat COMT specificity differs; deposition includes an inhibitor analog rather than CGA.
nutrient_topic
Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. · Chlorogenic acid / 5-O-caffeoylquinic acid
organism
Homo sapiens
plain_language
The shared methyl donor links COMT to methionine-cycle metabolism.
primary_references
[chlorogenic_acid-p18486144] Crystal structures of human 108V and 108M catechol O-methyltransferase. (2008). https://pubmed.ncbi.nlm.nih.gov/18486144/ DOI: 10.1016/j.jmb.2008.04.040
tissue_or_cell_type
Purified soluble COMT
Chlorogenic acid: metabolism, signaling and nutrient connections (2026-09-17) · lines 841–852
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human soluble COMT crystallography and deposited structure 3BWM · source_derived_draft · unverified_draft
### chlorogenic_acid-human-comt-sam Human soluble COMT structures resolve bound SAM. Condition category: normal nutrient_topic: Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: The shared methyl donor links COMT to methionine-cycle metabolism. organism: Homo sapiens tissue_or_cell_type: Purified soluble COMT experimental_model: Human soluble COMT crystallography and deposited structure 3BWM limitations: Structural cofactor connection, not a CGA-magnesium supplementation trial. Human and rat COMT specificity differs; deposition includes an inhibitor analog rather than CGA. exposure: SAM and 3,5-dinitrocatechol-bound crystals; deposited Mg ion evidence_span: {"source_cache": "artifacts/chlorogenic_acid-research/18486144.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "9cafbfc9353f49fab9919bc64608f21f445ace4b190771e44088a5a746e5a6e3", "start_char": 0, "end_char": 1961, "text_sha256": "9cafbfc9353f49fab9919bc64608f21f445ace4b190771e44088a5a746e5a6e3"} [chlorogenic_acid-p18486144] Crystal structures of human 108V and 108M catechol O-methyltransferase. (2008). https://pubmed.ncbi.nlm.nih.gov/18486144/ DOI: 10.1016/j.jmb.2008.04.040
Complete structured claim and evidence
The human COMT structure 3BWM includes bound magnesium alongside SAM and the catechol analog.
Human catechol O-methyltransferase / COMT → Mg2+ source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/chlorogenic_acid-research/3BWM.cif", "source_url": "https://files.rcsb.org/download/3BWM.cif", "locator": "Primary deposited structure 3BWM chemical-component loop; zero-based end-exclusive Unicode offsets", "file_sha256": "debe2736e6c5affecce595281fac469cd424ab6e91a5d908ec89d9460f60e4f6", "start_char": 11428, "end_char": 13476, "text_sha256": "98319e36f43f3fe147a2b9a2444809c31b0e14ae68e789fe3c1a8303fd8da8bc"}
experimental_model
Human soluble COMT crystallography and deposited structure 3BWM
exposure
SAM and 3,5-dinitrocatechol-bound crystals; deposited Mg ion
limitations
Structural cofactor connection, not a CGA-magnesium supplementation trial. Human and rat COMT specificity differs; deposition includes an inhibitor analog rather than CGA.
nutrient_topic
Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. · Chlorogenic acid / 5-O-caffeoylquinic acid
organism
Homo sapiens
plain_language
Magnesium is part of the measured enzyme complex; this does not prove that CGA depletes magnesium.
primary_references
[chlorogenic_acid-p18486144] Crystal structures of human 108V and 108M catechol O-methyltransferase. (2008). https://pubmed.ncbi.nlm.nih.gov/18486144/ DOI: 10.1016/j.jmb.2008.04.040
tissue_or_cell_type
Purified soluble COMT
Chlorogenic acid: metabolism, signaling and nutrient connections (2026-09-17) · lines 854–865
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human soluble COMT crystallography and deposited structure 3BWM · source_derived_draft · unverified_draft
### chlorogenic_acid-human-comt-mg The human COMT structure 3BWM includes bound magnesium alongside SAM and the catechol analog. Condition category: normal nutrient_topic: Chlorogenic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Magnesium is part of the measured enzyme complex; this does not prove that CGA depletes magnesium. organism: Homo sapiens tissue_or_cell_type: Purified soluble COMT experimental_model: Human soluble COMT crystallography and deposited structure 3BWM limitations: Structural cofactor connection, not a CGA-magnesium supplementation trial. Human and rat COMT specificity differs; deposition includes an inhibitor analog rather than CGA. exposure: SAM and 3,5-dinitrocatechol-bound crystals; deposited Mg ion evidence_span: {"source_cache": "artifacts/chlorogenic_acid-research/3BWM.cif", "source_url": "https://files.rcsb.org/download/3BWM.cif", "locator": "Primary deposited structure 3BWM chemical-component loop; zero-based end-exclusive Unicode offsets", "file_sha256": "debe2736e6c5affecce595281fac469cd424ab6e91a5d908ec89d9460f60e4f6", "start_char": 11428, "end_char": 13476, "text_sha256": "98319e36f43f3fe147a2b9a2444809c31b0e14ae68e789fe3c1a8303fd8da8bc"} [chlorogenic_acid-p18486144] Crystal structures of human 108V and 108M catechol O-methyltransferase. (2008). https://pubmed.ncbi.nlm.nih.gov/18486144/ DOI: 10.1016/j.jmb.2008.04.040
Complete structured claim and evidence
Human SIRT1 removes acetylation from histone H4 Lys16 in an NAD+-dependent reaction.
SIRT1 → Histone H4 acetylated at K16 source_derived_draftungraded
Experimental context and source evidence
experimental_model
Human enzyme assays and cultured-cell SIRT1 perturbation.
limitations
This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome.
organism
Human
plain_language
A different enzyme removes a lysine modification using NAD+.
primary_references
[sirt1-2004] Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin (2004). https://pubmed.ncbi.nlm.nih.gov/15469825/ DOI: 10.1016/j.molcel.2004.08.031
tissue_or_cell_type
Not specified as a whole tissue; see experimental model.
L-Lysine: mechanism-first literature curation (2026-09-17) · lines 537–545
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human enzyme assays and cultured-cell SIRT1 perturbation. · source_derived_draft · unverified_draft
### sirt1-h4k16-deacetylation Human SIRT1 removes acetylation from histone H4 Lys16 in an NAD+-dependent reaction. Plain language: A different enzyme removes a lysine modification using NAD+. Condition category: normal organism: Human tissue_or_cell_type: Not specified as a whole tissue; see experimental model. experimental_model: Human enzyme assays and cultured-cell SIRT1 perturbation. limitations: This reaction modifies lysine already in a protein. It does not show that extra oral lysine increases the reaction or improves a clinical outcome. [sirt1-2004] Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin (2004). https://pubmed.ncbi.nlm.nih.gov/15469825/ DOI: 10.1016/j.molcel.2004.08.031
Complete structured claim and evidence
EGCG showed ATP-competitive inhibition with Ki 320 nanomolar in the reported enzyme assay.
Epigallocatechin-3-gallate (EGCG) → Human mechanistic target of rapamycin kinase / MTOR source_derived_draftungraded
Experimental context and source evidence
experimental_model
Biochemical kinase assays plus MDA-MB-231 and A549 cell experiments.
limitations
PI3K isoform is not assigned from abstract; docking is a model, not a solved ligand structure.
nutrient_topic
EGCG collection; comparator and shared-pathway records retain their actual intervention. · Epigallocatechin-3-gallate (EGCG)
plain_language
EGCG competed with the enzyme’s energy substrate.
primary_references
Epigallocatechin gallate (EGCG), a major component of green tea, is a dual phosphoinositide-3-kinase/mTOR inhibitor. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21300025/ · DOI 10.1016/j.bbrc.2011.02.010
EGCG: receptor signaling, metabolism, nutrient interactions and discovery questions (2026-09-18) · lines 220–226
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Biochemical kinase assays plus MDA-MB-231 and A549 cell experiments. · source_derived_draft · unverified_draft
## egcg-mtor EGCG competed with the enzyme’s energy substrate. EGCG showed ATP-competitive inhibition with Ki 320 nanomolar in the reported enzyme assay. Model: Biochemical kinase assays plus MDA-MB-231 and A549 cell experiments. Limitations: PI3K isoform is not assigned from abstract; docking is a model, not a solved ligand structure. Evidence access: primary abstract. Epigallocatechin gallate (EGCG), a major component of green tea, is a dual phosphoinositide-3-kinase/mTOR inhibitor. · 2011 · https://pubmed.ncbi.nlm.nih.gov/21300025/ · DOI 10.1016/j.bbrc.2011.02.010
Complete structured claim and evidence
IFN-gamma/IDO-driven tryptophan depletion reduced S6K phosphorylation in human HeLa cells; tryptophan repletion restored the mTOR readout.
Human indoleamine 2,3-dioxygenase 1 / IDO1 → Human mechanistic target of rapamycin kinase / MTOR source_derived_draftungraded
Experimental context and source evidence
availability_state
nutrient_deficiency Imported condition classification; unverified.
evidence_access
Primary full text, Figure 2
experimental_model
Human HeLa cells, depleted media and amino-acid add-back.
limitations
S6K phosphorylation is a pathway readout, not direct tryptophan binding to MTOR.
nutrient_topic
Tryptophan collection; molecular form, preparation, species, exposure and manipulation remain explicit. · L-Tryptophan
plain_language
Local depletion reduced a growth signal as well as changing metabolite supply.
primary_references
IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23264892/ · DOI 10.4161/onci.21716
trigger_kind
nutrient_deficiency Imported condition classification; unverified.
Tryptophan: transport, protein synthesis, neuroactive metabolites, NAD and microbial pathways (2026-09-19) · lines 402–408
AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human HeLa cells, depleted media and amino-acid add-back. · source_derived_draft · unverified_draft
## tryptophan-trp-mtor Local depletion reduced a growth signal as well as changing metabolite supply. IFN-gamma/IDO-driven tryptophan depletion reduced S6K phosphorylation in human HeLa cells; tryptophan repletion restored the mTOR readout. Model: Human HeLa cells, depleted media and amino-acid add-back. Limitations: S6K phosphorylation is a pathway readout, not direct tryptophan binding to MTOR. Evidence access: Primary full text, Figure 2 IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel IDO effector pathway targeted by D-1-methyl-tryptophan. · 2012 · https://pubmed.ncbi.nlm.nih.gov/23264892/ · DOI 10.4161/onci.21716
Complete structured claim and evidence
Human hxCTb required 4F2hc for sodium-independent cystine/glutamate transport in oocytes.
SLC7A11 → Cystine source_derived_draftungraded
Experimental context and source evidence
evidence_span
{"source_cache": "artifacts/glutathione-research/11406111.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e7118afd8c6055ed926ee24dbb7a07538f676163d605115ae0d32d49fbef7fdc", "start_char": 0, "end_char": 1364, "text_sha256": "e7118afd8c6055ed926ee24dbb7a07538f676163d605115ae0d32d49fbef7fdc"}
experimental_model
Human xCT expression and oxidative-stress response
exposure
hxCTb with 4F2hc; diethyl maleate challenge
limitations
Sodium independence belongs to this transporter; other cysteine-entry routes differ.
nutrient_topic
Glutathione research collection; topical membership is not evidence of a direct dietary effect. · GSH
organism
Human transporter; Xenopus expression host
plain_language
The precursor-entry route depends on two transporter subunits.
primary_references
[glutathione-p11406111] Human cystine/glutamate transporter: cDNA cloning and upregulation by oxidative stress in glioma cells. (2001). https://pubmed.ncbi.nlm.nih.gov/11406111/ DOI: 10.1016/s0005-2736(01)00338-8
tissue_or_cell_type
Oocyte membranes and human U87 glioma cells
transport_effect
depends The record names the cystine/glutamate exchange pair and the 4F2hc requirement, not which way cystine crossed.
transport_pool
the cytosol across the plasma membrane The record names the cystine/glutamate exchange pair and the 4F2hc requirement, not which way cystine crossed.
Glutathione: metabolism, signaling and nutrient connections (2026-09-17) · lines 736–747
AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Human xCT expression and oxidative-stress response · source_derived_draft · unverified_draft
### glutathione-xct-cystine Human hxCTb required 4F2hc for sodium-independent cystine/glutamate transport in oocytes. Condition category: normal nutrient_topic: Glutathione research collection; topical membership is not evidence of a direct dietary effect. plain_language: The precursor-entry route depends on two transporter subunits. organism: Human transporter; Xenopus expression host tissue_or_cell_type: Oocyte membranes and human U87 glioma cells experimental_model: Human xCT expression and oxidative-stress response limitations: Sodium independence belongs to this transporter; other cysteine-entry routes differ. exposure: hxCTb with 4F2hc; diethyl maleate challenge evidence_span: {"source_cache": "artifacts/glutathione-research/11406111.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "e7118afd8c6055ed926ee24dbb7a07538f676163d605115ae0d32d49fbef7fdc", "start_char": 0, "end_char": 1364, "text_sha256": "e7118afd8c6055ed926ee24dbb7a07538f676163d605115ae0d32d49fbef7fdc"} [glutathione-p11406111] Human cystine/glutamate transporter: cDNA cloning and upregulation by oxidative stress in glioma cells. (2001). https://pubmed.ncbi.nlm.nih.gov/11406111/ DOI: 10.1016/s0005-2736(01)00338-8
Complete structured claim and evidence

Availability and dependencies

Each situation shows the normal role first, then what the sources report under a specific condition. A shortfall in the diet, a fault in the machinery, and a low blood reading are kept separate because they are not the same thing.

Glutathione responses depend on the regulator and stress state

Condition: machinery_impairment · ATF4 or Nrf2 siRNA in mouse cells.