Fisetin

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

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

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

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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

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

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

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

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

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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

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.

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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

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

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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

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

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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

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

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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

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.

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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

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

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

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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

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

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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

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

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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

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

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

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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

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

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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

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

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

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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

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

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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

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

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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

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

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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

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

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

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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

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

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

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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

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

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

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

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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

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

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

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

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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

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

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

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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

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

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

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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

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

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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

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

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

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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

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

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

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

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

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

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

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

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

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

Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 144–150

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

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

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

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

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

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

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

Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 72–78

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

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

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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

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

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

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

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

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

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.

Fisetin: metabolism, cell-state responses and cross-nutrient mechanisms (2026-09-19) · lines 64–70

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

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

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

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