GPX4

availability_state

Selenium restriction becomes severe enough to compromise GPX4 function in a susceptible context.

experimental_scope

Cell and cancer-model evidence for parallel defenses; GPX4 may be relatively preserved during nutritional restriction.

limitations

The source does not establish a nutritional dose or plasma value that disables GPX4. GPX4 deletion or drug inhibition is not equivalent to ordinary dietary deficiency; parallel protection is not guaranteed in every cell.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 119–123

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

Why GPX4 is especially important GPX4 directly reduces phospholipid hydroperoxides in membranes and is a central suppressor of ferroptosis. Severe loss of GPX4 function can therefore have consequences very different from loss of a more dispensable peroxide-removing enzyme. But GPX4 is not the only barrier between a cell and ferroptosis. The FSP1–CoQ10 system provides a parallel, glutathione-independent defense by regenerating reduced CoQ, which can trap lipid radicals. Other systems also contribute. Evidence: cell and cancer-model experiments. [8,9]

availability_state

Selenium status changes in an immune context; GPX4 perturbation studies test specific downstream defenses.

experimental_scope

Much of the detailed mechanism comes from cell and animal models; human immune findings are heterogeneous.

limitations

A GPX4 knockout does not specify the response to dietary restriction. No single immune cascade explains every supplementation result, and no clinical immunity cutoff is inferred.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 358–362

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

T-cell subsets GPX4-dependent control of lipid peroxidation can affect survival and differentiation Cell/animal

cross_nutrient

true

evidence_location

Primary abstract

experimental_model

Radiolabeled sterol analysis in erythrocyte ghosts

exposure

Photooxidation followed by GSH/PHGPX.

limitations

Product co-migration and assay-specific relative kinetics; no universal cellular rate.

nutrient_topic

Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E

organism

Human-derived cell-free membranes

plain_language

The enzyme also removed peroxide groups from oxidized cholesterol, more slowly than from phospholipids in this preparation.

primary_references

[ver-thomas1990] Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. In situ reduction of phospholipid and cholesterol hydroperoxides. (1990). https://pubmed.ncbi.nlm.nih.gov/2294113/ DOI: 10.1016/s0021-9258(19)40252-4

tissue_or_cell_type

Erythrocyte ghosts

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 564–576

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Radiolabeled sterol analysis in erythrocyte ghosts · source_derived_draft · unverified_draft

### ver-gpx4-cholesterol-hydroperoxide GSH/PHGPX reduced membrane cholesterol hydroperoxides, predominantly the photo-generated 5-alpha product, to diol-like products; cholesterol hydroperoxide decay was about one-sixth the phospholipid hydroperoxide decay rate in the ghost-membrane assay. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: The enzyme also removed peroxide groups from oxidized cholesterol, more slowly than from phospholipids in this preparation. organism: Human-derived cell-free membranes tissue_or_cell_type: Erythrocyte ghosts experimental_model: Radiolabeled sterol analysis in erythrocyte ghosts limitations: Product co-migration and assay-specific relative kinetics; no universal cellular rate. exposure: Photooxidation followed by GSH/PHGPX. cross_nutrient: true evidence_location: Primary abstract [ver-thomas1990] Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. In situ reduction of phospholipid and cholesterol hydroperoxides. (1990). https://pubmed.ncbi.nlm.nih.gov/2294113/ DOI: 10.1016/s0021-9258(19)40252-4

cross_nutrient

true

evidence_location

Primary abstract

experimental_model

Rose-bengal photoperoxidation followed by enzyme treatment

exposure

GSH/PHGPX after photooxidation.

limitations

Purified-enzyme preparation; distinguishes peroxide removal from vitamin E radical trapping.

nutrient_topic

Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E

organism

Human-derived cell-free membranes

plain_language

GPX4 removed peroxide groups from membrane phospholipids using glutathione.

primary_references

[ver-thomas1990] Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. In situ reduction of phospholipid and cholesterol hydroperoxides. (1990). https://pubmed.ncbi.nlm.nih.gov/2294113/ DOI: 10.1016/s0021-9258(19)40252-4

tissue_or_cell_type

Erythrocyte ghosts

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 550–562

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Rose-bengal photoperoxidation followed by enzyme treatment · source_derived_draft · unverified_draft

### ver-gpx4-pl-hydroperoxide-reduction Purified PHGPX (GPX4) with glutathione reduced phospholipid hydroperoxides within photooxidized human erythrocyte ghost membranes to alcohol products without prior phospholipase cleavage. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: GPX4 removed peroxide groups from membrane phospholipids using glutathione. organism: Human-derived cell-free membranes tissue_or_cell_type: Erythrocyte ghosts experimental_model: Rose-bengal photoperoxidation followed by enzyme treatment limitations: Purified-enzyme preparation; distinguishes peroxide removal from vitamin E radical trapping. exposure: GSH/PHGPX after photooxidation. cross_nutrient: true evidence_location: Primary abstract [ver-thomas1990] Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. In situ reduction of phospholipid and cholesterol hydroperoxides. (1990). https://pubmed.ncbi.nlm.nih.gov/2294113/ DOI: 10.1016/s0021-9258(19)40252-4

cross_nutrient

true

evidence_location

Primary abstract

experimental_model

Sequential peroxide reduction and iron challenge

exposure

Photoperoxidation → GSH/PHGPX → iron-dependent challenge.

limitations

Ascorbate participates in this deliberately pro-oxidizing assay; this is not evidence that normal vitamin C intake damages membranes.

nutrient_topic

Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E

organism

Human-derived cell-free membranes

plain_language

Removing membrane hydroperoxides prevented an iron-driven burst of further oxidation.

primary_references

[ver-thomas1990] Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. In situ reduction of phospholipid and cholesterol hydroperoxides. (1990). https://pubmed.ncbi.nlm.nih.gov/2294113/ DOI: 10.1016/s0021-9258(19)40252-4

tissue_or_cell_type

Erythrocyte ghosts

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 578–590

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Sequential peroxide reduction and iron challenge · source_derived_draft · unverified_draft

### ver-peroxide-removal-iron-burst GSH/PHGPX pretreatment completely suppressed the subsequent radical-peroxidation burst when photooxidized erythrocyte ghosts were challenged with ascorbate/iron or xanthine/xanthine-oxidase/iron. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing membrane hydroperoxides prevented an iron-driven burst of further oxidation. organism: Human-derived cell-free membranes tissue_or_cell_type: Erythrocyte ghosts experimental_model: Sequential peroxide reduction and iron challenge limitations: Ascorbate participates in this deliberately pro-oxidizing assay; this is not evidence that normal vitamin C intake damages membranes. exposure: Photoperoxidation → GSH/PHGPX → iron-dependent challenge. cross_nutrient: true evidence_location: Primary abstract [ver-thomas1990] Protective action of phospholipid hydroperoxide glutathione peroxidase against membrane-damaging lipid peroxidation. In situ reduction of phospholipid and cholesterol hydroperoxides. (1990). https://pubmed.ncbi.nlm.nih.gov/2294113/ DOI: 10.1016/s0021-9258(19)40252-4

evidence_span

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experimental_model

Metabolomics, chemoproteomics, perturbation and cancer-cell sensitivity profiling

exposure

Two classes of ferroptosis-inducing compounds

limitations

Preclinical drug-response mechanism; selenium or vitamin E supplementation is not established as a universal treatment.

nutrient_topic

Iron research collection; topical membership is not evidence of a direct dietary effect. · Iron

organism

Human cancer-cell lines and mouse xenografts

plain_language

The protective enzyme specifically controlled this iron-linked death pathway in the tested cells.

primary_references

[iron-p24439385] Regulation of ferroptotic cancer cell death by GPX4. (2014). https://pubmed.ncbi.nlm.nih.gov/24439385/ DOI: 10.1016/j.cell.2013.12.010

tissue_or_cell_type

Glutathione/GPX4 antioxidant system

Iron: absorption, trafficking, iron-dependent enzymes and nutrient interactions (2026-09-17) · lines 1265–1276

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolomics, chemoproteomics, perturbation and cancer-cell sensitivity profiling · source_derived_draft · unverified_draft

### iron-gpx4-ferroptosis GPX4 overexpression or knockdown altered lethality of all 12 tested ferroptosis inducers, but not 11 compounds with other lethal mechanisms. Condition category: normal nutrient_topic: Iron research collection; topical membership is not evidence of a direct dietary effect. plain_language: The protective enzyme specifically controlled this iron-linked death pathway in the tested cells. organism: Human cancer-cell lines and mouse xenografts tissue_or_cell_type: Glutathione/GPX4 antioxidant system experimental_model: Metabolomics, chemoproteomics, perturbation and cancer-cell sensitivity profiling limitations: Preclinical drug-response mechanism; selenium or vitamin E supplementation is not established as a universal treatment. exposure: Two classes of ferroptosis-inducing compounds evidence_span: {"source_cache": "artifacts/iron-research/24439385.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f8d588af38ec5438fbec80971ead0764466237b3382492051aa3b3c297841703", "start_char": 0, "end_char": 957, "text_sha256": "f8d588af38ec5438fbec80971ead0764466237b3382492051aa3b3c297841703"} [iron-p24439385] Regulation of ferroptotic cancer cell death by GPX4. (2014). https://pubmed.ncbi.nlm.nih.gov/24439385/ DOI: 10.1016/j.cell.2013.12.010

cell_type

B1 and marginal-zone B cells

experimental_model

Mouse B-cell-specific Gpx4 deletion

limitations

Does not prove ordinary human dietary deficiency deletes these subsets.

organism

Mus musculus

Selenium: literature corrections and mechanism additions · lines 1324–1334

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Mouse B-cell-specific Gpx4 deletion · secondary_verified · secondary_verified

## b1-gpx4 These B-cell subsets need GPX4 protection in the mouse experiments. Gpx4 protects B1 and marginal-zone B cells against lipid peroxidation and ferroptosis in tested mouse deletion models. Organism: Mus musculus Cell type: B1 and marginal-zone B cells Experimental model: Mouse B-cell-specific Gpx4 deletion Limitations: Does not prove ordinary human dietary deficiency deletes these subsets. Primary reference: [B1 and Marginal Zone B Cells but Not Follicular B2 Cells Require Gpx4 to Prevent Lipid Peroxidation and Ferroptosis](https://pubmed.ncbi.nlm.nih.gov/31775041/)

cell_type

Follicular B2 and germinal-center B cells

experimental_model

Mouse B-cell-specific Gpx4 deletion

limitations

Restricted to tested genetic/immunization conditions, not universal dispensability.

organism

Mus musculus

Selenium: literature corrections and mechanism additions · lines 1336–1346

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Mouse B-cell-specific Gpx4 deletion · secondary_verified · secondary_verified

## b2-gpx4-context The same deletion did not eliminate the measured germinal-center response. Follicular B2 development, germinal-center reactions and antibody responses were preserved after B-cell Gpx4 deletion in the tested mice. Organism: Mus musculus Cell type: Follicular B2 and germinal-center B cells Experimental model: Mouse B-cell-specific Gpx4 deletion Limitations: Restricted to tested genetic/immunization conditions, not universal dispensability. Primary reference: [B1 and Marginal Zone B Cells but Not Follicular B2 Cells Require Gpx4 to Prevent Lipid Peroxidation and Ferroptosis](https://pubmed.ncbi.nlm.nih.gov/31775041/)

cell_type

Follicular helper T cells

experimental_model

Mouse T-cell/Tfh experiments and young-adult influenza vaccination study

limitations

Not B-cell-intrinsic or proof of all vaccine effects; interpret corrected article.

organism

Mus musculus

Selenium: literature corrections and mechanism additions · lines 1348–1358

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Mouse T-cell/Tfh experiments and young-adult influenza vaccination study · secondary_verified · secondary_verified

## tfh-gpx4 Protection of helper T cells is a distinct route to supporting antibody responses. GPX4 protects follicular helper T cells from ferroptosis in the studied T-cell-specific models. Organism: Mus musculus Cell type: Follicular helper T cells Experimental model: Mouse T-cell/Tfh experiments and young-adult influenza vaccination study Limitations: Not B-cell-intrinsic or proof of all vaccine effects; interpret corrected article. Primary reference: [Selenium-GPX4 axis protects follicular helper T cells from ferroptosis](https://www.nature.com/articles/s41590-021-00996-0)

evidence_span

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experimental_model

Cell perturbation and xenograft experiments

exposure

DIM; NRF2 overexpression and pharmacological rescue controls

limitations

Preclinical cancer context. Reduced defense here differs from Nrf2 induction in fibroblasts; neither result proves a universal antioxidant or prooxidant effect in people.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human non-small-cell lung-cancer cells and mouse xenografts

plain_language

A particular tumor context showed suppression of this defense/signaling component.

primary_references

[dim-p40100489] 3,3'-diindolylmethane induces ferroptosis and inhibits proliferation in non-small-cell lung cancer through the AHR/NRF2/GPX4 axis. (2025). https://pubmed.ncbi.nlm.nih.gov/40100489/ DOI: 10.1007/s12672-025-02096-z

tissue_or_cell_type

Ferroptosis and AHR/NRF2/GPX4

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 1312–1323

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell perturbation and xenograft experiments · source_derived_draft · unverified_draft

### dim-nsclc-gpx4 DIM treatment reduced GPX4 in the tested lung-cancer models. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: A particular tumor context showed suppression of this defense/signaling component. organism: Human non-small-cell lung-cancer cells and mouse xenografts tissue_or_cell_type: Ferroptosis and AHR/NRF2/GPX4 experimental_model: Cell perturbation and xenograft experiments limitations: Preclinical cancer context. Reduced defense here differs from Nrf2 induction in fibroblasts; neither result proves a universal antioxidant or prooxidant effect in people. exposure: DIM; NRF2 overexpression and pharmacological rescue controls evidence_span: {"source_cache": "artifacts/dim-research/40100489.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "99bc986298e026c4bd40745004936bab65af37a931084f75634b89505f5b95d0", "start_char": 0, "end_char": 1722, "text_sha256": "99bc986298e026c4bd40745004936bab65af37a931084f75634b89505f5b95d0"} [dim-p40100489] 3,3'-diindolylmethane induces ferroptosis and inhibits proliferation in non-small-cell lung cancer through the AHR/NRF2/GPX4 axis. (2025). https://pubmed.ncbi.nlm.nih.gov/40100489/ DOI: 10.1007/s12672-025-02096-z

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_access

Primary full text

experimental_model

Human HepG2 loss/gain-of-function experiments.

limitations

Not a selective rescue test proving all luteolin effects require SLC7A11.

nutrient_topic

Luteolin collection; molecular form, preparation, species, exposure and manipulation remain explicit. · Luteolin / 3′,4′,5,7-tetrahydroxyflavone

plain_language

Precursor handling and peroxide defense are linked.

primary_references

Luteolin attenuates CCl4-induced hepatic injury by inhibiting ferroptosis via SLC7A11. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38755566/ · DOI 10.1186/s12906-024-04486-2

trigger_kind

machinery_impairment Imported condition classification; unverified.

Luteolin: metabolism, immune signaling, redox chemistry and cross-nutrient mechanisms (2026-09-19) · lines 524–530

AI-assisted research curation; primary-abstract references and experimental limitations individually identified. Not publisher full text. · supports · Human HepG2 loss/gain-of-function experiments. · source_derived_draft · unverified_draft

## luteolin-slc7a11-knockdown Precursor handling and peroxide defense are linked. SLC7A11 silencing lowered GPX4/FTMT expression and total glutathione while worsening ferroptosis-associated measurements in HepG2 cells. Model: Human HepG2 loss/gain-of-function experiments. Limitations: Not a selective rescue test proving all luteolin effects require SLC7A11. Evidence access: Primary full text Luteolin attenuates CCl4-induced hepatic injury by inhibiting ferroptosis via SLC7A11. · 2024 · https://pubmed.ncbi.nlm.nih.gov/38755566/ · DOI 10.1186/s12906-024-04486-2

evidence_access

Primary abstract

experimental_model

Human nasopharyngeal-cancer cells; animal tumor work also reported.

limitations

Expression is not direct GPX4 binding or evidence of selenium depletion.

nutrient_topic

Cucurbitacins collection; species, compartment, exposure, co-substrates and manipulation remain explicit. · Cucurbitacins

plain_language

A lipid-peroxide defense protein decreased in this model.

primary_references

Induction of ferroptosis in human nasopharyngeal cancer cells by cucurbitacin B: molecular mechanism and therapeutic potential. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33664249/ · DOI 10.1038/s41419-021-03516-y

Cucurbitacins: thiol chemistry, cytoskeleton, metabolic dependencies and signaling (2026-09-20) · lines 244–250

AI-assisted research curation; primary references, access levels and experimental limitations individually identified. Not publisher full text. · supports · Human nasopharyngeal-cancer cells; animal tumor work also reported. · source_derived_draft · unverified_draft

## cucurbitacin-b-gpx4-expression A lipid-peroxide defense protein decreased in this model. Cucurbitacin B exposure decreased GPX4 protein expression in the human nasopharyngeal-cancer experiments. Model: Human nasopharyngeal-cancer cells; animal tumor work also reported. Limitations: Expression is not direct GPX4 binding or evidence of selenium depletion. Evidence access: Primary abstract Induction of ferroptosis in human nasopharyngeal cancer cells by cucurbitacin B: molecular mechanism and therapeutic potential. · 2021 · https://pubmed.ncbi.nlm.nih.gov/33664249/ · DOI 10.1038/s41419-021-03516-y

availability_state

Selenium supply is restricted for a defined tissue, species, and duration.

experimental_scope

Predominantly animal and cell models; ranking varies with tissue, species, development, duration, and measurement.

limitations

Relative preservation does not mean immunity to severe loss. Um34 alone does not implement a universal ranking, and no plasma-to-protein cutoff is assigned.

trigger_kind

nutrient_deficiency

Selenium deficiency: a mechanism-first reference · lines 101–117

Supplied selenium deficiency reference · supports · Supplied reference; verify the primary study and experimental context. · source_derived_draft · unverified_draft

2.1 Protein hierarchy: useful, but schematic Different selenoproteins respond differently to selenium restriction. A useful conceptual grouping is: More selenium-responsive in many models Intermediate / context-dependent Relatively preserved in severe restriction GPX1, SELENOW GPX3, SELENOP, DIO1, SELENOK, SELENOM GPX4, TXNRD1, DIO2, SEPHS2 This is a schematic hierarchy, not a literal universal sequence of death. Ordering varies with tissue, species, developmental stage, duration of deficiency, and how the endpoint is measured.

cross_nutrient

Shared GPX4 connects retinoid signaling to the selenium collection; no proven supplementation synergy.

experimental_model

HT-1080 cells; pharmacological ATRA.

limitations

Direct promoter binding and dietary selenium replacement were not tested.

nutrient_topic

Vitamin A research collection; topical membership is not evidence of a direct dietary effect. · Vitamin A

organism

Homo sapiens

plain_language

Retinoid signaling reached existing ferroptosis-defense machinery.

primary_references

[va-berndt2024] Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development (2024). https://pubmed.ncbi.nlm.nih.gov/39218970/ DOI: 10.1038/s41467-024-51996-1

tissue_or_cell_type

Human cell line

Vitamin A: forms, mechanisms, deficiency and excess (2026-09-17) · lines 1811–1821

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · HT-1080 cells; pharmacological ATRA. · source_derived_draft · unverified_draft

### va-atra-ferroptosis-regulators ATRA increased GPX4/FSP1 protein and GCH1 transcripts; RAR blockade suppressed the transcript responses. Condition category: normal nutrient_topic: Vitamin A research collection; topical membership is not evidence of a direct dietary effect. plain_language: Retinoid signaling reached existing ferroptosis-defense machinery. organism: Homo sapiens tissue_or_cell_type: Human cell line experimental_model: HT-1080 cells; pharmacological ATRA. limitations: Direct promoter binding and dietary selenium replacement were not tested. cross_nutrient: Shared GPX4 connects retinoid signaling to the selenium collection; no proven supplementation synergy. [va-berndt2024] Suppression of ferroptosis by vitamin A or radical-trapping antioxidants is essential for neuronal development (2024). https://pubmed.ncbi.nlm.nih.gov/39218970/ DOI: 10.1038/s41467-024-51996-1

evidence_span

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experimental_model

Metabolomics, chemoproteomics, perturbation and cancer-cell sensitivity profiling

exposure

Two classes of ferroptosis-inducing compounds

limitations

Preclinical drug-response mechanism; selenium or vitamin E supplementation is not established as a universal treatment.

nutrient_topic

Iron research collection; topical membership is not evidence of a direct dietary effect. · Iron

organism

Human cancer-cell lines and mouse xenografts

plain_language

Losing the antioxidant substrate and directly blocking its enzyme are different routes into the same vulnerability.

primary_references

[iron-p24439385] Regulation of ferroptotic cancer cell death by GPX4. (2014). https://pubmed.ncbi.nlm.nih.gov/24439385/ DOI: 10.1016/j.cell.2013.12.010

tissue_or_cell_type

Glutathione/GPX4 antioxidant system

Iron: absorption, trafficking, iron-dependent enzymes and nutrient interactions (2026-09-17) · lines 1252–1263

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolomics, chemoproteomics, perturbation and cancer-cell sensitivity profiling · source_derived_draft · unverified_draft

### iron-gsh-gpx-loss Glutathione depletion in response to one class of ferroptosis inducers inactivated glutathione peroxidases, while another class directly inhibited GPX4. Condition category: normal nutrient_topic: Iron research collection; topical membership is not evidence of a direct dietary effect. plain_language: Losing the antioxidant substrate and directly blocking its enzyme are different routes into the same vulnerability. organism: Human cancer-cell lines and mouse xenografts tissue_or_cell_type: Glutathione/GPX4 antioxidant system experimental_model: Metabolomics, chemoproteomics, perturbation and cancer-cell sensitivity profiling limitations: Preclinical drug-response mechanism; selenium or vitamin E supplementation is not established as a universal treatment. exposure: Two classes of ferroptosis-inducing compounds evidence_span: {"source_cache": "artifacts/iron-research/24439385.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "f8d588af38ec5438fbec80971ead0764466237b3382492051aa3b3c297841703", "start_char": 0, "end_char": 957, "text_sha256": "f8d588af38ec5438fbec80971ead0764466237b3382492051aa3b3c297841703"} [iron-p24439385] Regulation of ferroptotic cancer cell death by GPX4. (2014). https://pubmed.ncbi.nlm.nih.gov/24439385/ DOI: 10.1016/j.cell.2013.12.010

evidence_span

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experimental_model

Cell perturbation and xenograft experiments

exposure

DIM; NRF2 overexpression and pharmacological rescue controls

limitations

Preclinical cancer context. Reduced defense here differs from Nrf2 induction in fibroblasts; neither result proves a universal antioxidant or prooxidant effect in people.

nutrient_topic

Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. · 3,3'-Diindolylmethane / DIM

organism

Human non-small-cell lung-cancer cells and mouse xenografts

plain_language

Perturbation controls helped connect the response to specific defenses.

primary_references

[dim-p40100489] 3,3'-diindolylmethane induces ferroptosis and inhibits proliferation in non-small-cell lung cancer through the AHR/NRF2/GPX4 axis. (2025). https://pubmed.ncbi.nlm.nih.gov/40100489/ DOI: 10.1007/s12672-025-02096-z

tissue_or_cell_type

Ferroptosis and AHR/NRF2/GPX4

Diindolylmethane (DIM): formation, receptor signaling, metabolism and drug interactions (2026-09-17) · lines 1351–1362

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cell perturbation and xenograft experiments · source_derived_draft · unverified_draft

### dim-nsclc-ferroptosis DIM induced ferroptosis that could be reversed by ferrostatin-1, NAC or the tested AHR antagonist; NRF2 overexpression also reversed it. Condition category: normal nutrient_topic: Diindolylmethane (DIM) research collection; topical membership is not evidence of a direct dietary effect. plain_language: Perturbation controls helped connect the response to specific defenses. organism: Human non-small-cell lung-cancer cells and mouse xenografts tissue_or_cell_type: Ferroptosis and AHR/NRF2/GPX4 experimental_model: Cell perturbation and xenograft experiments limitations: Preclinical cancer context. Reduced defense here differs from Nrf2 induction in fibroblasts; neither result proves a universal antioxidant or prooxidant effect in people. exposure: DIM; NRF2 overexpression and pharmacological rescue controls evidence_span: {"source_cache": "artifacts/dim-research/40100489.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "99bc986298e026c4bd40745004936bab65af37a931084f75634b89505f5b95d0", "start_char": 0, "end_char": 1722, "text_sha256": "99bc986298e026c4bd40745004936bab65af37a931084f75634b89505f5b95d0"} [dim-p40100489] 3,3'-diindolylmethane induces ferroptosis and inhibits proliferation in non-small-cell lung cancer through the AHR/NRF2/GPX4 axis. (2025). https://pubmed.ncbi.nlm.nih.gov/40100489/ DOI: 10.1007/s12672-025-02096-z

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/coq10-research/33981038.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b1af5a97412b5ebf797083a069385c4ed98258e68845692732448bfe061a453b", "start_char": 0, "end_char": 1716, "text_sha256": "b1af5a97412b5ebf797083a069385c4ed98258e68845692732448bfe061a453b"}

experimental_model

Genetic and pharmacological cancer-cell studies

exposure

DHODH loss or brequinar, with GPX4 inhibition

limitations

Pharmacological attribution and relative DHODH contribution were directly challenged in 2023; preserve the dispute rather than generalizing to dietary CoQ effects.

nutrient_topic

Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. · Coenzyme Q10 / CoQ10 redox system

organism

Human cancer-cell and tumor models

plain_language

The effect depended on which other defense route remained available.

primary_references

[coq10-p33981038] DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. (2021). https://pubmed.ncbi.nlm.nih.gov/33981038/ DOI: 10.1038/s41586-021-03539-7

tissue_or_cell_type

Mitochondrial ferroptosis defense

trigger_kind

machinery_impairment Imported condition classification; unverified.

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 827–838

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Genetic and pharmacological cancer-cell studies · source_derived_draft · unverified_draft

### coq10-dhodh-loss DHODH inactivation increased mitochondrial lipid peroxidation and ferroptosis in the reported GPX4-dependent experimental contexts. Condition category: machinery_impairment nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The effect depended on which other defense route remained available. organism: Human cancer-cell and tumor models tissue_or_cell_type: Mitochondrial ferroptosis defense experimental_model: Genetic and pharmacological cancer-cell studies limitations: Pharmacological attribution and relative DHODH contribution were directly challenged in 2023; preserve the dispute rather than generalizing to dietary CoQ effects. exposure: DHODH loss or brequinar, with GPX4 inhibition evidence_span: {"source_cache": "artifacts/coq10-research/33981038.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b1af5a97412b5ebf797083a069385c4ed98258e68845692732448bfe061a453b", "start_char": 0, "end_char": 1716, "text_sha256": "b1af5a97412b5ebf797083a069385c4ed98258e68845692732448bfe061a453b"} [coq10-p33981038] DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. (2021). https://pubmed.ncbi.nlm.nih.gov/33981038/ DOI: 10.1038/s41586-021-03539-7

evidence_span

{"source_cache": "artifacts/coq10-research/33981038.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b1af5a97412b5ebf797083a069385c4ed98258e68845692732448bfe061a453b", "start_char": 0, "end_char": 1716, "text_sha256": "b1af5a97412b5ebf797083a069385c4ed98258e68845692732448bfe061a453b"}

experimental_model

Genetic and pharmacological cancer-cell studies

exposure

DHODH loss or brequinar, with GPX4 inhibition

limitations

Pharmacological attribution and relative DHODH contribution were directly challenged in 2023; preserve the dispute rather than generalizing to dietary CoQ effects.

nutrient_topic

Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. · Coenzyme Q10 / CoQ10 redox system

organism

Human cancer-cell and tumor models

plain_language

A pyrimidine-synthesis enzyme can also contribute reduced CoQ in the studied system.

primary_references

[coq10-p33981038] DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. (2021). https://pubmed.ncbi.nlm.nih.gov/33981038/ DOI: 10.1038/s41586-021-03539-7

tissue_or_cell_type

Mitochondrial ferroptosis defense

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 814–825

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Genetic and pharmacological cancer-cell studies · source_derived_draft · unverified_draft

### coq10-dhodh-quinol The study reported DHODH-dependent ubiquinol generation as a mitochondrial ferroptosis-defense pathway. Condition category: normal nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: A pyrimidine-synthesis enzyme can also contribute reduced CoQ in the studied system. organism: Human cancer-cell and tumor models tissue_or_cell_type: Mitochondrial ferroptosis defense experimental_model: Genetic and pharmacological cancer-cell studies limitations: Pharmacological attribution and relative DHODH contribution were directly challenged in 2023; preserve the dispute rather than generalizing to dietary CoQ effects. exposure: DHODH loss or brequinar, with GPX4 inhibition evidence_span: {"source_cache": "artifacts/coq10-research/33981038.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "b1af5a97412b5ebf797083a069385c4ed98258e68845692732448bfe061a453b", "start_char": 0, "end_char": 1716, "text_sha256": "b1af5a97412b5ebf797083a069385c4ed98258e68845692732448bfe061a453b"} [coq10-p33981038] DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. (2021). https://pubmed.ncbi.nlm.nih.gov/33981038/ DOI: 10.1038/s41586-021-03539-7

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/coq10-research/35749365.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8d8219ff3cd63697715c88c25a9e558315bcd95c25bbc38f76987544bfee7581", "start_char": 0, "end_char": 1142, "text_sha256": "8d8219ff3cd63697715c88c25a9e558315bcd95c25bbc38f76987544bfee7581"}

experimental_model

Metabolomics, genetic deletion and tumor experiments

exposure

G3P supply and GPD2/GPX4 loss

limitations

Preclinical mechanism; no evidence that glycerol or CoQ supplements treat cancer.

nutrient_topic

Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. · Coenzyme Q10 / CoQ10 redox system

organism

Cancer-cell and tumor models

plain_language

Dependence on one pathway changed when the parallel defense was blocked.

primary_references

[coq10-p35749365] A ferroptosis defense mechanism mediated by glycerol-3-phosphate dehydrogenase 2 in mitochondria. (2022). https://pubmed.ncbi.nlm.nih.gov/35749365/ DOI: 10.1073/pnas.2121987119

tissue_or_cell_type

Mitochondrial glycerol-phosphate oxidation

trigger_kind

machinery_impairment Imported condition classification; unverified.

Coenzyme Q10: biosynthesis, electron transfer, antioxidant recycling and nutrient interactions (2026-09-17) · lines 866–877

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Metabolomics, genetic deletion and tumor experiments · source_derived_draft · unverified_draft

### coq10-gpd2-loss GPD2 deletion sensitized cancer cells to GPX4-inhibition-induced mitochondrial lipid peroxidation and ferroptosis. Condition category: machinery_impairment nutrient_topic: Coenzyme Q10 research collection; topical membership is not evidence of a direct dietary effect. plain_language: Dependence on one pathway changed when the parallel defense was blocked. organism: Cancer-cell and tumor models tissue_or_cell_type: Mitochondrial glycerol-phosphate oxidation experimental_model: Metabolomics, genetic deletion and tumor experiments limitations: Preclinical mechanism; no evidence that glycerol or CoQ supplements treat cancer. exposure: G3P supply and GPD2/GPX4 loss evidence_span: {"source_cache": "artifacts/coq10-research/35749365.abstract.txt", "locator": "Primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "8d8219ff3cd63697715c88c25a9e558315bcd95c25bbc38f76987544bfee7581", "start_char": 0, "end_char": 1142, "text_sha256": "8d8219ff3cd63697715c88c25a9e558315bcd95c25bbc38f76987544bfee7581"} [coq10-p35749365] A ferroptosis defense mechanism mediated by glycerol-3-phosphate dehydrogenase 2 in mitochondria. (2022). https://pubmed.ncbi.nlm.nih.gov/35749365/ DOI: 10.1073/pnas.2121987119

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/k2-research/35922516.fulltext.txt", "locator": "Exact primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a75e4881732cbe87173197db393b42d49fc6e8110df919fed8d63b16c9877da6", "start_char": 16083, "end_char": 16259, "text_sha256": "942e81f7fca3a59aecc9d6cfcdc008e88931de54074e63eeb96c71af3d236eec"}

experimental_model

Enzyme/liposome chemistry, knockout cells and warfarin-exposed mice

exposure

MK-4/K1, NAD(P)H, FSP1 loss and inhibitors

limitations

Preclinical experiments; not a demonstrated oral MK-7 treatment for ferroptosis-related disease or a self-treatment regimen for anticoagulant poisoning.

nutrient_topic

Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. · Vitamin K2 / menaquinone family

organism

Human recombinant FSP1, mammalian cells and mice

plain_language

The FSP1 pathway and selenium-dependent GPX4 defense are connected but not the same mechanism.

primary_references

[k2-p35922516] A non-canonical vitamin K cycle is a potent ferroptosis suppressor. (2022). https://pubmed.ncbi.nlm.nih.gov/35922516/ DOI: 10.1038/s41586-022-05022-3

tissue_or_cell_type

Lipid peroxidation and vitamin K reduction

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin K2: menaquinone forms, carboxylation, recycling and nutrient interactions (2026-09-17) · lines 812–823

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Enzyme/liposome chemistry, knockout cells and warfarin-exposed mice · source_derived_draft · unverified_draft

### k2-fsp1-gpx4-parallel Cells lacking both GPX4 and FSP1 required higher K1/MK-4 concentrations to prevent ferroptosis than cells lacking GPX4 alone. Condition category: machinery_impairment nutrient_topic: Vitamin K2 research collection; topical membership is not evidence of a direct dietary effect. plain_language: The FSP1 pathway and selenium-dependent GPX4 defense are connected but not the same mechanism. organism: Human recombinant FSP1, mammalian cells and mice tissue_or_cell_type: Lipid peroxidation and vitamin K reduction experimental_model: Enzyme/liposome chemistry, knockout cells and warfarin-exposed mice limitations: Preclinical experiments; not a demonstrated oral MK-7 treatment for ferroptosis-related disease or a self-treatment regimen for anticoagulant poisoning. exposure: MK-4/K1, NAD(P)H, FSP1 loss and inhibitors evidence_span: {"source_cache": "artifacts/k2-research/35922516.fulltext.txt", "locator": "Exact primary full-text span; zero-based, end-exclusive Unicode character offsets", "file_sha256": "a75e4881732cbe87173197db393b42d49fc6e8110df919fed8d63b16c9877da6", "start_char": 16083, "end_char": 16259, "text_sha256": "942e81f7fca3a59aecc9d6cfcdc008e88931de54074e63eeb96c71af3d236eec"} [k2-p35922516] A non-canonical vitamin K cycle is a potent ferroptosis suppressor. (2022). https://pubmed.ncbi.nlm.nih.gov/35922516/ DOI: 10.1038/s41586-022-05022-3

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs

exposure

HA-tagged rescue constructs; Figure 6j: 48-hour RSL3 challenge, n=3 independent experiments. Exact RSL3 concentrations follow the figure dose response and are not inferred here.

limitations

C2S affects APT2 palmitoylation/localization and is not identical to the S122A catalytic-site perturbation. Null comparisons do not prove equivalence. No sulforaphane or solasonine tested in this rescue experiment.

organism

Human

primary_locator

Figure 6i-j; Results: Inhibition of APT2 suppresses ferroptosis.

primary_references

https://doi.org/10.1038/s41467-025-56344-5

trigger_kind

machinery_impairment Imported condition classification; unverified.

APT2, STAT3 and GPX4: opposing branches and assay qualification · lines 33–39

Primary observations: 10.1038/s41467-025-56344-5 and 10.1002/ptr.70245; selected full-text review 2026-09-20. · supports · Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs · source_derived_draft · unverified_draft

C2S APT2 re-expression did not reproduce wild-type restoration of RSL3 susceptibility in APT2-depleted A375 cells. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 6i-j; Results: Inhibition of APT2 suppresses ferroptosis. organism: Human experimental_model: Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs exposure: HA-tagged rescue constructs; Figure 6j: 48-hour RSL3 challenge, n=3 independent experiments. Exact RSL3 concentrations follow the figure dose response and are not inferred here. limitations: C2S affects APT2 palmitoylation/localization and is not identical to the S122A catalytic-site perturbation. Null comparisons do not prove equivalence. No sulforaphane or solasonine tested in this rescue experiment.

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs

exposure

HA-tagged rescue constructs; Figure 6j: 48-hour RSL3 challenge, n=3 independent experiments. Exact RSL3 concentrations follow the figure dose response and are not inferred here.

limitations

C2S affects APT2 palmitoylation/localization and is not identical to the S122A catalytic-site perturbation. Null comparisons do not prove equivalence. No sulforaphane or solasonine tested in this rescue experiment.

organism

Human

primary_locator

Figure 6i-j; Results: Inhibition of APT2 suppresses ferroptosis.

primary_references

https://doi.org/10.1038/s41467-025-56344-5

trigger_kind

machinery_impairment Imported condition classification; unverified.

APT2, STAT3 and GPX4: opposing branches and assay qualification · lines 24–30

Primary observations: 10.1038/s41467-025-56344-5 and 10.1002/ptr.70245; selected full-text review 2026-09-20. · supports · Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs · source_derived_draft · unverified_draft

C2S APT2 re-expression did not reproduce the wild-type reduction in GPX4 protein in APT2-depleted A375 cells. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 6i-j; Results: Inhibition of APT2 suppresses ferroptosis. organism: Human experimental_model: Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs exposure: HA-tagged rescue constructs; Figure 6j: 48-hour RSL3 challenge, n=3 independent experiments. Exact RSL3 concentrations follow the figure dose response and are not inferred here. limitations: C2S affects APT2 palmitoylation/localization and is not identical to the S122A catalytic-site perturbation. Null comparisons do not prove equivalence. No sulforaphane or solasonine tested in this rescue experiment.

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs

exposure

HA-tagged rescue constructs; Figure 6j: 48-hour RSL3 challenge, n=3 independent experiments. Exact RSL3 concentrations follow the figure dose response and are not inferred here.

limitations

C2S affects APT2 palmitoylation/localization and is not identical to the S122A catalytic-site perturbation. Null comparisons do not prove equivalence. No sulforaphane or solasonine tested in this rescue experiment.

organism

Human

primary_locator

Figure 6i-j; Results: Inhibition of APT2 suppresses ferroptosis.

primary_references

https://doi.org/10.1038/s41467-025-56344-5

trigger_kind

machinery_impairment Imported condition classification; unverified.

APT2, STAT3 and GPX4: opposing branches and assay qualification · lines 51–57

Primary observations: 10.1038/s41467-025-56344-5 and 10.1002/ptr.70245; selected full-text review 2026-09-20. · supports · Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs · source_derived_draft · unverified_draft

S122A APT2 re-expression did not reproduce wild-type restoration of RSL3 susceptibility in APT2-depleted A375 cells. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 6i-j; Results: Inhibition of APT2 suppresses ferroptosis. organism: Human experimental_model: Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs exposure: HA-tagged rescue constructs; Figure 6j: 48-hour RSL3 challenge, n=3 independent experiments. Exact RSL3 concentrations follow the figure dose response and are not inferred here. limitations: C2S affects APT2 palmitoylation/localization and is not identical to the S122A catalytic-site perturbation. Null comparisons do not prove equivalence. No sulforaphane or solasonine tested in this rescue experiment.

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs

exposure

HA-tagged rescue constructs; Figure 6j: 48-hour RSL3 challenge, n=3 independent experiments. Exact RSL3 concentrations follow the figure dose response and are not inferred here.

limitations

C2S affects APT2 palmitoylation/localization and is not identical to the S122A catalytic-site perturbation. Null comparisons do not prove equivalence. No sulforaphane or solasonine tested in this rescue experiment.

organism

Human

primary_locator

Figure 6i-j; Results: Inhibition of APT2 suppresses ferroptosis.

primary_references

https://doi.org/10.1038/s41467-025-56344-5

trigger_kind

machinery_impairment Imported condition classification; unverified.

APT2, STAT3 and GPX4: opposing branches and assay qualification · lines 42–48

Primary observations: 10.1038/s41467-025-56344-5 and 10.1002/ptr.70245; selected full-text review 2026-09-20. · supports · Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs · source_derived_draft · unverified_draft

S122A APT2 re-expression did not reproduce the wild-type reduction in GPX4 protein in APT2-depleted A375 cells. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 6i-j; Results: Inhibition of APT2 suppresses ferroptosis. organism: Human experimental_model: Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs exposure: HA-tagged rescue constructs; Figure 6j: 48-hour RSL3 challenge, n=3 independent experiments. Exact RSL3 concentrations follow the figure dose response and are not inferred here. limitations: C2S affects APT2 palmitoylation/localization and is not identical to the S122A catalytic-site perturbation. Null comparisons do not prove equivalence. No sulforaphane or solasonine tested in this rescue experiment.

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs

exposure

HA-tagged rescue constructs; Figure 6j: 48-hour RSL3 challenge, n=3 independent experiments. Exact RSL3 concentrations follow the figure dose response and are not inferred here.

limitations

C2S affects APT2 palmitoylation/localization and is not identical to the S122A catalytic-site perturbation. Null comparisons do not prove equivalence. No sulforaphane or solasonine tested in this rescue experiment.

organism

Human

primary_locator

Figure 6i-j; Results: Inhibition of APT2 suppresses ferroptosis.

primary_references

https://doi.org/10.1038/s41467-025-56344-5

trigger_kind

machinery_impairment Imported condition classification; unverified.

APT2, STAT3 and GPX4: opposing branches and assay qualification · lines 15–21

Primary observations: 10.1038/s41467-025-56344-5 and 10.1002/ptr.70245; selected full-text review 2026-09-20. · supports · Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs · source_derived_draft · unverified_draft

Wild-type APT2 re-expression restored RSL3 susceptibility in APT2-depleted A375 cells. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 6i-j; Results: Inhibition of APT2 suppresses ferroptosis. organism: Human experimental_model: Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs exposure: HA-tagged rescue constructs; Figure 6j: 48-hour RSL3 challenge, n=3 independent experiments. Exact RSL3 concentrations follow the figure dose response and are not inferred here. limitations: C2S affects APT2 palmitoylation/localization and is not identical to the S122A catalytic-site perturbation. Null comparisons do not prove equivalence. No sulforaphane or solasonine tested in this rescue experiment.

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs

exposure

HA-tagged rescue constructs; Figure 6j: 48-hour RSL3 challenge, n=3 independent experiments. Exact RSL3 concentrations follow the figure dose response and are not inferred here.

limitations

C2S affects APT2 palmitoylation/localization and is not identical to the S122A catalytic-site perturbation. Null comparisons do not prove equivalence. No sulforaphane or solasonine tested in this rescue experiment.

organism

Human

primary_locator

Figure 6i-j; Results: Inhibition of APT2 suppresses ferroptosis.

primary_references

https://doi.org/10.1038/s41467-025-56344-5

trigger_kind

machinery_impairment Imported condition classification; unverified.

APT2, STAT3 and GPX4: opposing branches and assay qualification · lines 6–12

Primary observations: 10.1038/s41467-025-56344-5 and 10.1002/ptr.70245; selected full-text review 2026-09-20. · supports · Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs · source_derived_draft · unverified_draft

Wild-type APT2 re-expression lowered GPX4 protein in APT2-depleted A375 cells. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 6i-j; Results: Inhibition of APT2 suppresses ferroptosis. organism: Human experimental_model: Human A375 melanoma cells with APT2 shRNA and lentiviral rescue constructs exposure: HA-tagged rescue constructs; Figure 6j: 48-hour RSL3 challenge, n=3 independent experiments. Exact RSL3 concentrations follow the figure dose response and are not inferred here. limitations: C2S affects APT2 palmitoylation/localization and is not identical to the S122A catalytic-site perturbation. Null comparisons do not prove equivalence. No sulforaphane or solasonine tested in this rescue experiment.

experimental_model

Human NOZ and GBC-SD gallbladder cancer cells

exposure

Methods 2.2 describes 48-hour cellular drug treatments with refresh at 24 hours; exact concentration must be checked per figure and is not inferred from another assay.

limitations

Human cancer-cell experiments; no clinical or dietary inference. Solasonine exposure is not equivalent to APT2 depletion, ML349, or sulforaphane. Mutant rescue does not by itself establish selectivity or normal baseline mutant function. Figure 5C calls this APT2 activity, but Methods 2.17 describes an anti-LYPLA2 ELISA with mass-concentration standards and an HRP/TMB readout from cell supernatants. No direct APT2 substrate-turnover assay is described there. The result is retained as an author-labelled activity proxy, not established catalytic inhibition. This methodological qualification does not invalidate the separately reported binding or cellular observations.

organism

Human

primary_locator

Figure 3I; Results 3.3; ChIP evidence in Figure 3E-H.

primary_references

https://doi.org/10.1002/ptr.70245

APT2, STAT3 and GPX4: opposing branches and assay qualification · lines 123–129

Primary observations: 10.1038/s41467-025-56344-5 and 10.1002/ptr.70245; selected full-text review 2026-09-20. · supports · Human NOZ and GBC-SD gallbladder cancer cells · source_derived_draft · unverified_draft

Solasonine suppressed STAT3-driven GPX4 wild-type promoter reporter activity; binding-motif mutations abolished the reported responses. primary_references: https://doi.org/10.1002/ptr.70245 primary_locator: Figure 3I; Results 3.3; ChIP evidence in Figure 3E-H. organism: Human experimental_model: Human NOZ and GBC-SD gallbladder cancer cells exposure: Methods 2.2 describes 48-hour cellular drug treatments with refresh at 24 hours; exact concentration must be checked per figure and is not inferred from another assay. limitations: Human cancer-cell experiments; no clinical or dietary inference. Solasonine exposure is not equivalent to APT2 depletion, ML349, or sulforaphane. Mutant rescue does not by itself establish selectivity or normal baseline mutant function. Figure 5C calls this APT2 activity, but Methods 2.17 describes an anti-LYPLA2 ELISA with mass-concentration standards and an HRP/TMB readout from cell supernatants. No direct APT2 substrate-turnover assay is described there. The result is retained as an author-labelled activity proxy, not established catalytic inhibition. This methodological qualification does not invalidate the separately reported binding or cellular observations.

availability_state

machinery_impairment Imported condition classification; unverified.

experimental_model

Human NOZ and GBC-SD gallbladder cancer cells

exposure

siSTAT3 versus control; reciprocal STAT3 overexpression increased mRNA/protein in the same reported figure group. Transfection duration not independently resolved here.

limitations

Human cancer-cell experiments; no clinical or dietary inference. Solasonine exposure is not equivalent to APT2 depletion, ML349, or sulforaphane. Mutant rescue does not by itself establish selectivity or normal baseline mutant function. Figure 5C calls this APT2 activity, but Methods 2.17 describes an anti-LYPLA2 ELISA with mass-concentration standards and an HRP/TMB readout from cell supernatants. No direct APT2 substrate-turnover assay is described there. The result is retained as an author-labelled activity proxy, not established catalytic inhibition. This methodological qualification does not invalidate the separately reported binding or cellular observations.

organism

Human

primary_locator

Figure 3A-D and Supplementary Figure S3A-B; Results 3.3.

primary_references

https://doi.org/10.1002/ptr.70245

trigger_kind

machinery_impairment Imported condition classification; unverified.

APT2, STAT3 and GPX4: opposing branches and assay qualification · lines 141–147

Primary observations: 10.1038/s41467-025-56344-5 and 10.1002/ptr.70245; selected full-text review 2026-09-20. · supports · Human NOZ and GBC-SD gallbladder cancer cells · source_derived_draft · unverified_draft

STAT3 siRNA reduced GPX4 mRNA in the reported gallbladder cancer-cell experiments. primary_references: https://doi.org/10.1002/ptr.70245 primary_locator: Figure 3A-D and Supplementary Figure S3A-B; Results 3.3. organism: Human experimental_model: Human NOZ and GBC-SD gallbladder cancer cells exposure: siSTAT3 versus control; reciprocal STAT3 overexpression increased mRNA/protein in the same reported figure group. Transfection duration not independently resolved here. limitations: Human cancer-cell experiments; no clinical or dietary inference. Solasonine exposure is not equivalent to APT2 depletion, ML349, or sulforaphane. Mutant rescue does not by itself establish selectivity or normal baseline mutant function. Figure 5C calls this APT2 activity, but Methods 2.17 describes an anti-LYPLA2 ELISA with mass-concentration standards and an HRP/TMB readout from cell supernatants. No direct APT2 substrate-turnover assay is described there. The result is retained as an author-labelled activity proxy, not established catalytic inhibition. This methodological qualification does not invalidate the separately reported binding or cellular observations.

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_cache

artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc

experimental_model

Human A375 and HT1080 cancer cells; lentiviral APT2 shRNA

exposure

RT-qPCR; three independent experiments; exposure timing unresolved.

limitations

These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. The actor names the A375 arm; the parallel HT1080 observation is preserved in the context. No transcriptional effect is inferred.

organism

Human experimental cells; construct species unresolved where stated for discussion-only nulls

primary_locator

Figure 5f

primary_references

https://doi.org/10.1038/s41467-025-56344-5

source_access

Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis.

trigger_kind

machinery_impairment Imported condition classification; unverified.

APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 129–137

Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human A375 and HT1080 cancer cells; lentiviral APT2 shRNA · source_derived_draft · unverified_draft

APT2 knockdown did not significantly change GPX4 mRNA in the reported A375 and HT1080 RT-qPCR experiments. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 5f source_access: Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc experimental_model: Human A375 and HT1080 cancer cells; lentiviral APT2 shRNA organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: RT-qPCR; three independent experiments; exposure timing unresolved. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. The actor names the A375 arm; the parallel HT1080 observation is preserved in the context. No transcriptional effect is inferred.

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_cache

artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc

experimental_model

Human A375 melanoma; lentiviral APT2 shRNA; exogenous GPX4

exposure

ABE assay with and without hydroxylamine; representative of three independent experiments; exact shRNA exposure duration unresolved.

limitations

These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. The Results prose calls this deletion, but Figure 5d specifies shRNA; record the figure-defined knockdown, not a knockout.

organism

Human experimental cells; construct species unresolved where stated for discussion-only nulls

primary_locator

Figure 5d and Results: APT2 mediates the depalmitoylation of GPX4

primary_references

https://doi.org/10.1038/s41467-025-56344-5

source_access

Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis.

trigger_kind

machinery_impairment Imported condition classification; unverified.

APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 107–115

Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human A375 melanoma; lentiviral APT2 shRNA; exogenous GPX4 · source_derived_draft · unverified_draft

APT2 shRNA increased GPX4 palmitoylation measured by acyl-biotin exchange in A375 cells. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 5d and Results: APT2 mediates the depalmitoylation of GPX4 source_access: Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc experimental_model: Human A375 melanoma; lentiviral APT2 shRNA; exogenous GPX4 organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: ABE assay with and without hydroxylamine; representative of three independent experiments; exact shRNA exposure duration unresolved. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. The Results prose calls this deletion, but Figure 5d specifies shRNA; record the figure-defined knockdown, not a knockout.

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_cache

artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc

experimental_model

Human A375 melanoma; lentiviral APT2 shRNA

exposure

Cycloheximide chase; three independent experiments; exact CHX concentration and time series not resolved from reviewed legend.

limitations

These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements.

organism

Human experimental cells; construct species unresolved where stated for discussion-only nulls

primary_locator

Figure 5i,j

primary_references

https://doi.org/10.1038/s41467-025-56344-5

source_access

Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis.

trigger_kind

machinery_impairment Imported condition classification; unverified.

APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 118–126

Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human A375 melanoma; lentiviral APT2 shRNA · source_derived_draft · unverified_draft

APT2 knockdown increased GPX4 protein stability in A375 cycloheximide-chase experiments. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 5i,j source_access: Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc experimental_model: Human A375 melanoma; lentiviral APT2 shRNA organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: Cycloheximide chase; three independent experiments; exact CHX concentration and time series not resolved from reviewed legend. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements.

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_cache

artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc

experimental_model

Human A375 melanoma; lentiviral APT2 shRNA

exposure

4 micromolar RSL3 for 6 hours; SYTOX Green staining; three independent experiments.

limitations

These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. This is a response to a GPX4 inhibitor in cancer cells. It does not establish an effect of sulforaphane or dietary selenium.

organism

Human experimental cells; construct species unresolved where stated for discussion-only nulls

primary_locator

Figure 6c,d

primary_references

https://doi.org/10.1038/s41467-025-56344-5

source_access

Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis.

trigger_kind

machinery_impairment Imported condition classification; unverified.

APT2: sulforaphane engagement, GPX4 stability and ZDHHC6 turnover · lines 140–148

Targeted primary-literature curation from recursive ZDHHC6 exploration, 2026-09-20. · supports · Human A375 melanoma; lentiviral APT2 shRNA · source_derived_draft · unverified_draft

APT2 knockdown reduced RSL3-induced cell death measured with SYTOX Green in A375 cells. primary_references: https://doi.org/10.1038/s41467-025-56344-5 primary_locator: Figure 6c,d source_access: Selected primary Results and Figure 5/6 legends reviewed. No supplement or raw-data reanalysis. evidence_cache: artifacts/discovery-research/round6-sources/gpx4-primary-passages.json; SHA256 384aaae29ec0e6fe9814782b3e5d885753751fa1b2bbd103e30e8ffa113df5dc experimental_model: Human A375 melanoma; lentiviral APT2 shRNA organism: Human experimental cells; construct species unresolved where stated for discussion-only nulls exposure: 4 micromolar RSL3 for 6 hours; SYTOX Green staining; three independent experiments. limitations: These are separate experimental observations, not a demonstrated sulforaphane-GPX4-ZDHHC6 pathway. Sulforaphane-driven APT2 relocalization is not equivalent to genetic depletion or general catalytic inhibition. No dietary, clinical or selenium-repletion effect is inferred. Protein stability, palmitoylation and substrate output remain different measurements. This is a response to a GPX4 inhibitor in cancer cells. It does not establish an effect of sulforaphane or dietary selenium.

cross_nutrient

true

evidence_location

Figure 4B

experimental_model

RSL3 challenge and flow-cytometric C11-BODIPY assay

exposure

E forms at 1 and 30 µM for 1 h before 0.5 µM RSL3 for 2 h.

limitations

Potency in cell assays does not establish nutritional equivalence or human efficacy; the study also detected toxicity at higher concentrations, with tocotrienols toxic at lower concentrations than tocopherols. Probe oxidation is not a chemically resolved inventory of endogenous phospholipid products.

nutrient_topic

Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E

organism

Homo sapiens

plain_language

Alpha-tocotrienol more effectively limited the lipid-oxidation reporter in this cancer-cell assay.

primary_references

[ver-yang2026] Tocotrienols exhibit superior ferroptosis inhibition over tocopherols. (2026). https://pubmed.ncbi.nlm.nih.gov/41501350/ DOI: 10.1038/s41598-025-34673-1

tissue_or_cell_type

HT-1080 fibrosarcoma cells

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 802–814

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · RSL3 challenge and flow-cytometric C11-BODIPY assay · source_derived_draft · unverified_draft

### ver-alpha-t3-cellular-oxidation In HT-1080 cells challenged with the GPX4 inhibitor RSL3, alpha-tocotrienol suppressed the oxidized C11-BODIPY signal at lower tested concentrations than alpha-tocopherol. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Alpha-tocotrienol more effectively limited the lipid-oxidation reporter in this cancer-cell assay. organism: Homo sapiens tissue_or_cell_type: HT-1080 fibrosarcoma cells experimental_model: RSL3 challenge and flow-cytometric C11-BODIPY assay limitations: Potency in cell assays does not establish nutritional equivalence or human efficacy; the study also detected toxicity at higher concentrations, with tocotrienols toxic at lower concentrations than tocopherols. Probe oxidation is not a chemically resolved inventory of endogenous phospholipid products. exposure: E forms at 1 and 30 µM for 1 h before 0.5 µM RSL3 for 2 h. cross_nutrient: true evidence_location: Figure 4B [ver-yang2026] Tocotrienols exhibit superior ferroptosis inhibition over tocopherols. (2026). https://pubmed.ncbi.nlm.nih.gov/41501350/ DOI: 10.1038/s41598-025-34673-1

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Primary abstract

experimental_model

Combined dietary depletion and 4-hydroxytamoxifen-induced deletion

exposure

Six-week vitamin E depletion preceding Gpx4 deletion.

limitations

Primary abstract only; vascular and survival endpoints in one mouse deletion model, not general human deficiency or dosing evidence.

nutrient_topic

Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E

organism

Mus musculus

plain_language

Removing dietary vitamin E exposed severe vascular injury in mice whose endothelial GPX4 was then deleted.

primary_references

[ver-wortmann2013] Combined deficiency in glutathione peroxidase 4 and vitamin E causes multiorgan thrombus formation and early death in mice. (2013). https://pubmed.ncbi.nlm.nih.gov/23770613/ DOI: 10.1161/circresaha.113.279984

tissue_or_cell_type

Multiorgan vascular endothelium

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 648–660

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Combined dietary depletion and 4-hydroxytamoxifen-induced deletion · source_derived_draft · unverified_draft

### ver-endo-combined-e-gpx4-loss Six weeks of vitamin E-depleted diet before inducible endothelial Gpx4 deletion led to endothelial detachment and cell death in multiple mouse organs, accompanied by thrombosis and approximately 80% knockout mortality. Condition category: nutrient_deficiency nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Removing dietary vitamin E exposed severe vascular injury in mice whose endothelial GPX4 was then deleted. organism: Mus musculus tissue_or_cell_type: Multiorgan vascular endothelium experimental_model: Combined dietary depletion and 4-hydroxytamoxifen-induced deletion limitations: Primary abstract only; vascular and survival endpoints in one mouse deletion model, not general human deficiency or dosing evidence. exposure: Six-week vitamin E depletion preceding Gpx4 deletion. cross_nutrient: true evidence_location: Primary abstract [ver-wortmann2013] Combined deficiency in glutathione peroxidase 4 and vitamin E causes multiorgan thrombus formation and early death in mice. (2013). https://pubmed.ncbi.nlm.nih.gov/23770613/ DOI: 10.1161/circresaha.113.279984

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Primary abstract

experimental_model

Endothelial Gpx4 conditional deletion

exposure

Normal diet; no quantitative vitamin E content assigned from abstract.

limitations

Primary abstract only; vascular and survival endpoints in one mouse deletion model, not general human deficiency or dosing evidence.

nutrient_topic

Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E

organism

Mus musculus

plain_language

Loss of endothelial GPX4 alone did not produce an obvious vascular phenotype under the normal-diet conditions tested.

primary_references

[ver-wortmann2013] Combined deficiency in glutathione peroxidase 4 and vitamin E causes multiorgan thrombus formation and early death in mice. (2013). https://pubmed.ncbi.nlm.nih.gov/23770613/ DOI: 10.1161/circresaha.113.279984

tissue_or_cell_type

Vascular endothelium

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 634–646

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Endothelial Gpx4 conditional deletion · source_derived_draft · unverified_draft

### ver-endo-gpx4-normal-diet Endothelium-specific Gpx4 deletion produced no obvious impairment of vascular homeostasis in mice maintained on a normal diet in the reported study. Condition category: machinery_impairment nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Loss of endothelial GPX4 alone did not produce an obvious vascular phenotype under the normal-diet conditions tested. organism: Mus musculus tissue_or_cell_type: Vascular endothelium experimental_model: Endothelial Gpx4 conditional deletion limitations: Primary abstract only; vascular and survival endpoints in one mouse deletion model, not general human deficiency or dosing evidence. exposure: Normal diet; no quantitative vitamin E content assigned from abstract. cross_nutrient: true evidence_location: Primary abstract [ver-wortmann2013] Combined deficiency in glutathione peroxidase 4 and vitamin E causes multiorgan thrombus formation and early death in mice. (2013). https://pubmed.ncbi.nlm.nih.gov/23770613/ DOI: 10.1161/circresaha.113.279984

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Figure 4d; Methods

experimental_model

Tamoxifen-inducible Gpx4 deletion with re-expression controls

exposure

1 µM tamoxifen for 48 h; 200 µM alpha-tocopherol for 24 h before repair assay.

limitations

Genetic GPX4 loss, not nutritional selenium deficiency; repair mechanism downstream of oxidation was not resolved.

nutrient_topic

Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E

organism

Mus musculus

plain_language

Vitamin E loading rescued membrane resealing after GPX4 deletion in these fibroblasts.

primary_references

[ver-labazi2015] The antioxidant requirement for plasma membrane repair in skeletal muscle. (2015). https://pubmed.ncbi.nlm.nih.gov/25843658/ DOI: 10.1016/j.freeradbiomed.2015.03.016

tissue_or_cell_type

Embryonic fibroblasts

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 718–730

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Tamoxifen-inducible Gpx4 deletion with re-expression controls · source_derived_draft · unverified_draft

### ver-gpx4-fibroblast-repair-rescue In mouse embryonic fibroblasts subjected to 48-hour inducible Gpx4 deletion, 200 µM alpha-tocopherol supplementation for the preceding 24 hours prevented the pronounced laser-wound repair defect. Condition category: machinery_impairment nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin E loading rescued membrane resealing after GPX4 deletion in these fibroblasts. organism: Mus musculus tissue_or_cell_type: Embryonic fibroblasts experimental_model: Tamoxifen-inducible Gpx4 deletion with re-expression controls limitations: Genetic GPX4 loss, not nutritional selenium deficiency; repair mechanism downstream of oxidation was not resolved. exposure: 1 µM tamoxifen for 48 h; 200 µM alpha-tocopherol for 24 h before repair assay. cross_nutrient: true evidence_location: Figure 4d; Methods [ver-labazi2015] The antioxidant requirement for plasma membrane repair in skeletal muscle. (2015). https://pubmed.ncbi.nlm.nih.gov/25843658/ DOI: 10.1016/j.freeradbiomed.2015.03.016

cross_nutrient

true

evidence_location

Primary abstract

experimental_model

Microsomes and Triton-dispersed lipid micelles

exposure

Iron-dependent peroxidation; physiological vitamin E:phospholipid ratio as reported in abstract.

limitations

Exact concentrations are not available in the inspected abstract. Model-specific dependence does not imply every membrane requires added GPX4 to show E protection.

nutrient_topic

Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E

organism

Rattus norvegicus

plain_language

Vitamin E protection depended on peroxide removal by the GPX4/glutathione system in these preparations.

primary_references

[ver-maiorino1989] Microsomal lipid peroxidation: effect of vitamin E and its functional interaction with phospholipid hydroperoxide glutathione peroxidase. (1989). https://pubmed.ncbi.nlm.nih.gov/2586229/ DOI: 10.1007/bf02535211

tissue_or_cell_type

Liver microsomal lipids

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 592–604

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Microsomes and Triton-dispersed lipid micelles · source_derived_draft · unverified_draft

### ver-gpx4-gsh-tocopherol-cooperation At a physiological vitamin E-to-phospholipid ratio, inhibition of iron-dependent lipid peroxidation in rat liver microsomes and dispersed microsomal lipids was observed only when PHGPX (GPX4) and glutathione were also present. Condition category: normal nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Vitamin E protection depended on peroxide removal by the GPX4/glutathione system in these preparations. organism: Rattus norvegicus tissue_or_cell_type: Liver microsomal lipids experimental_model: Microsomes and Triton-dispersed lipid micelles limitations: Exact concentrations are not available in the inspected abstract. Model-specific dependence does not imply every membrane requires added GPX4 to show E protection. exposure: Iron-dependent peroxidation; physiological vitamin E:phospholipid ratio as reported in abstract. cross_nutrient: true evidence_location: Primary abstract [ver-maiorino1989] Microsomal lipid peroxidation: effect of vitamin E and its functional interaction with phospholipid hydroperoxide glutathione peroxidase. (1989). https://pubmed.ncbi.nlm.nih.gov/2586229/ DOI: 10.1007/bf02535211

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Results/Table 2; standard-chow comparison Table 1

experimental_model

Alb-Cre conditional Gpx4 deletion and maternal diet

exposure

500 IU/kg DL-alpha-tocopheryl acetate during gestation/lactation; weaning at 3 weeks.

limitations

Alb-Cre Gpx4 loss is machinery impairment, not selenium deficiency; mouse survival rescue does not establish human substitutability.

nutrient_topic

Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E

organism

Mus musculus

plain_language

Extra dietary vitamin E rescued early survival in mice lacking liver GPX4.

primary_references

[ver-carlson2016] Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. (2016). https://pubmed.ncbi.nlm.nih.gov/27262435/ DOI: 10.1016/j.redox.2016.05.003

tissue_or_cell_type

Hepatocytes and whole-animal survival

trigger_kind

machinery_impairment Imported condition classification; unverified.

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 606–618

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Alb-Cre conditional Gpx4 deletion and maternal diet · source_derived_draft · unverified_draft

### ver-liver-gpx4-e-rescue Maternal dietary supplementation with 500 IU/kg DL-alpha-tocopheryl acetate through gestation and nursing allowed Alb-Cre;Gpx4fl/fl pups to survive to weaning, whereas liver-specific Gpx4-null pups on standard chow died within 48 hours after birth. Condition category: machinery_impairment nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: Extra dietary vitamin E rescued early survival in mice lacking liver GPX4. organism: Mus musculus tissue_or_cell_type: Hepatocytes and whole-animal survival experimental_model: Alb-Cre conditional Gpx4 deletion and maternal diet limitations: Alb-Cre Gpx4 loss is machinery impairment, not selenium deficiency; mouse survival rescue does not establish human substitutability. exposure: 500 IU/kg DL-alpha-tocopheryl acetate during gestation/lactation; weaning at 3 weeks. cross_nutrient: true evidence_location: Results/Table 2; standard-chow comparison Table 1 [ver-carlson2016] Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. (2016). https://pubmed.ncbi.nlm.nih.gov/27262435/ DOI: 10.1016/j.redox.2016.05.003

availability_state

nutrient_deficiency Imported condition classification; unverified.

cross_nutrient

true

evidence_location

Figures 4–5

experimental_model

Diet withdrawal after developmental rescue

exposure

E-enriched diet through 6 weeks; subsequent E withdrawal; necrosis examined after 3 weeks.

limitations

Alb-Cre Gpx4 loss is machinery impairment, not selenium deficiency; mouse survival rescue does not establish human substitutability.

nutrient_topic

Vitamin E research collection; topical membership is not evidence of a direct dietary effect. · Vitamin E

organism

Mus musculus

plain_language

The rescued mice remained dependent on continued vitamin E supply.

primary_references

[ver-carlson2016] Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. (2016). https://pubmed.ncbi.nlm.nih.gov/27262435/ DOI: 10.1016/j.redox.2016.05.003

tissue_or_cell_type

Liver

trigger_kind

nutrient_deficiency Imported condition classification; unverified.

Vitamin E: transport, membrane protection and nutrient interactions (2026-09-17) · lines 620–632

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Diet withdrawal after developmental rescue · source_derived_draft · unverified_draft

### ver-liver-gpx4-e-withdrawal After six weeks on vitamin E-enriched diets, switching liver-specific Gpx4-null mice to vitamin E-deficient diet caused extensive hepatocellular necrosis and loss of the prior survival rescue; control genotypes survived the monitored 78 days after withdrawal. Condition category: nutrient_deficiency nutrient_topic: Vitamin E research collection; topical membership is not evidence of a direct dietary effect. plain_language: The rescued mice remained dependent on continued vitamin E supply. organism: Mus musculus tissue_or_cell_type: Liver experimental_model: Diet withdrawal after developmental rescue limitations: Alb-Cre Gpx4 loss is machinery impairment, not selenium deficiency; mouse survival rescue does not establish human substitutability. exposure: E-enriched diet through 6 weeks; subsequent E withdrawal; necrosis examined after 3 weeks. cross_nutrient: true evidence_location: Figures 4–5 [ver-carlson2016] Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. (2016). https://pubmed.ncbi.nlm.nih.gov/27262435/ DOI: 10.1016/j.redox.2016.05.003

cell_type

cancer cell lines

experimental_model

Genetic disruption and ribosome analyses

limitations

Tumor-cell result; GPX4 priority is context dependent.

organism

human

Selenium: literature corrections and mechanism additions · lines 594–604

Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually · supports · Genetic disruption and ribosome analyses · secondary_verified · secondary_verified

## lrp8-loss-promotes-gpx4-stalling Disrupted selenium uptake hindered GPX4 production in these cancer cells. LRP8 loss caused GPX4 UGA-associated ribosome stalling in the tested cancer cells. Organism: human Cell type: cancer cell lines Experimental model: Genetic disruption and ribosome analyses Limitations: Tumor-cell result; GPX4 priority is context dependent. Primary reference: [Ribosome stalling during selenoprotein translation exposes a ferroptosis vulnerability](https://pubmed.ncbi.nlm.nih.gov/35637349/)