{"id":"bdbbca2b-7a79-5a44-9a20-1920b0b11d3b","stable_key":"availability:gpx4-parallel-ferroptosis-defense:1","predicate":"can_fail_to_control","statement":"When GPX4 function is severely reduced, its direct control of membrane phospholipid hydroperoxides is compromised.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"source_reported: Cell/biochemical and animal cancer models; supplied-source synthesis with a narrow FSP1 primary-study spot check.","direction":"negative","is_public":true,"mechanism_event_id":"17abb4a6-44a2-5948-9a1b-9eecc0a272ed","mechanism_event_label":"When GPX4 function is severely reduced, its direct control of membrane phospholipid hydroperoxides is compromised.","subject":{"id":"e9bb13ee-f238-51e6-9101-78ddfd11465c","slug":"gpx4","display_name":"GPX4","entity_type_key":"protein"},"object":{"id":"5b200520-e015-50ee-8fbf-e0e0707296f1","slug":"phospholipid-hydroperoxides","display_name":"Phospholipid hydroperoxides","entity_type_key":"lipid"},"evidence_count":1,"mechanism_event":{"id":"17abb4a6-44a2-5948-9a1b-9eecc0a272ed","stable_key":"availability:gpx4-parallel-ferroptosis-defense:1","event_type":"availability_dependent_change","label":"When GPX4 function is severely reduced, its direct control of membrane phospholipid hydroperoxides is compromised.","description":"Selenium restriction becomes severe enough to compromise GPX4 function in a susceptible context. Cell and cancer-model evidence for parallel defenses; GPX4 may be relatively preserved during nutritional restriction.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"e9bb13ee-f238-51e6-9101-78ddfd11465c","slug":"gpx4","display_name":"GPX4","entity_type_key":"protein"},"role":"condition_input","stoichiometry":null,"state_label":"Selenium restriction becomes severe enough to compromise GPX4 function in a susceptible context.","sequence_order":0,"notes":""},{"entity":{"id":"5b200520-e015-50ee-8fbf-e0e0707296f1","slug":"phospholipid-hydroperoxides","display_name":"Phospholipid hydroperoxides","entity_type_key":"lipid"},"role":"affected_component","stoichiometry":null,"state_label":"Selenium restriction becomes severe enough to compromise GPX4 function in a susceptible context.","sequence_order":1,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"Selenium restriction becomes severe enough to compromise GPX4 function in a susceptible context.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_scope","value_text":"Cell and cancer-model evidence for parallel defenses; GPX4 may be relatively preserved during nutritional restriction.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"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.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"nutrient_deficiency","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"51b4ef25-c176-5400-b02b-a9fce5633c55","evidence_kind":"source_passage","locator":"lines 119-123","start_line":119,"end_line":123,"excerpt":"Why GPX4 is especially important\n\nGPX4 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.\n\nBut 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]","model_system":"Supplied reference; verify the primary study and experimental context.","directness":"reported_statement","verification_status":"source_derived_draft","notes":"","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"c788c19c-884c-5233-92b1-0bd063d87741","stable_key":"deficiency","title":"Selenium deficiency: a mechanism-first reference","document_type":"user_supplied_reference","citation_label":"Supplied selenium deficiency reference","file_path":"X:\\metabolic-ledger\\source_material\\selenium-deficiency-reference.md","sha256":"a3f14bc3fa24c595dda830664523090a7b5bfa76e9dcf517f42f62212ceb767e","revision_id":"f8f97804-c1fb-56df-9c06-c02e36e2a5b8","review_status":"unverified_draft","notes":"Preserved verbatim. Reported study types are source labels, not independent verification."}}],"relations":[],"conflicts":[],"corrections":[{"id":"37492085-76af-53f1-876b-6f036840dab5","title":"GPX4 impairment does not make ferroptosis unconditional","kind":"qualification","status":"qualified","why":"The earlier molecular passage gives a direct GPX4 loss or selenium starvation to membrane rupture cascade. The new reference adds parallel FSP1–CoQ10 defense and other contributors.","resolution":"Present GPX4 as central to phospholipid peroxide control while making the outcome conditional on the cell and its other defenses. The older correction draft also already describes parallel axes; this qualification targets the unconditional molecular wording.","created_at":"2026-09-17 05:59:32","record_type":"qualification","display_label":"Source qualification","record_url":"/corrections/37492085-76af-53f1-876b-6f036840dab5","literature_review":{"revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1591,"end_line":1596,"papers":[{"paper_key":"bersuker-2019","title":"The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis","url":"https://www.nature.com/articles/s41586-019-1705-2","doi":"10.1038/s41586-019-1705-2","year":2019,"model":"Cell genetics and biochemical experiments","summary":"FSP1/CoQ provides parallel lipid-radical defense."}]},"sides":[{"conflict_id":"37492085-76af-53f1-876b-6f036840dab5","ordinal":0,"label":"Earlier statement","revision_id":"1fa1ebde-141f-5d47-8a4f-ba87ff84a6c6","start_line":89,"end_line":91,"quote":"**Cascade into ferroptosis:**\n\nPUFA (arachidonoyl) → **ACSL4** → esterified into PE → **LPCAT3** → **ALOX15** or Fe²⁺-driven autoxidation → **PE-AA-OOH** in the membrane → GPX4 reduces it to PE-AA-OH. Knock out GPX4, drug it (RSL3, ML162 — which covalently alkylate the selenolate *because* it's the best nucleophile around), or starve it of Se → hydroperoxides propagate → membrane rupture → ferroptosis.","claim_id":null,"source_key":"molecular","source_title":"Selenium: the molecular cascade","claim_ids":[]},{"conflict_id":"37492085-76af-53f1-876b-6f036840dab5","ordinal":1,"label":"New reference qualification","revision_id":"f8f97804-c1fb-56df-9c06-c02e36e2a5b8","start_line":119,"end_line":123,"quote":"Why GPX4 is especially important\n\nGPX4 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.\n\nBut 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]","claim_id":null,"source_key":"deficiency","source_title":"Selenium deficiency: a mechanism-first reference","claim_ids":[]}]}],"research":null}