{"id":"8624e937-f5a6-5ffc-9686-433bd7377f15","stable_key":"research:gpx4-cys-vulnerability","predicate":"increases_susceptibility_to","statement":"GPX4 Sec-to-Cys substitution retains context-dependent residual function but increases peroxide-induced inactivation and ferroptosis susceptibility.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"literature_reviewed:direct_experimental","direction":"positive","is_public":true,"mechanism_event_id":"53b0df58-1f52-57e8-8da9-561fa81221a7","mechanism_event_label":"Replacing selenium with sulfur retains some function but weakens peroxide resistance.","subject":{"id":"672a50bf-cfde-5306-a518-584543b5f4e2","slug":"gpx4-cys","display_name":"GPX4 Sec-to-Cys variant","entity_type_key":"protein_state"},"object":{"id":"85ca0bb8-8a67-59fe-8334-e0f6617380b7","slug":"ferroptosis","display_name":"Ferroptosis","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"53b0df58-1f52-57e8-8da9-561fa81221a7","stable_key":"research:gpx4-cys-vulnerability","event_type":"contextual_mechanism","label":"Replacing selenium with sulfur retains some function but weakens peroxide resistance.","description":"GPX4 Sec-to-Cys substitution retains context-dependent residual function but increases peroxide-induced inactivation and ferroptosis susceptibility.","status":"active","compartment":null,"participants":[{"entity":{"id":"672a50bf-cfde-5306-a518-584543b5f4e2","slug":"gpx4-cys","display_name":"GPX4 Sec-to-Cys variant","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"85ca0bb8-8a67-59fe-8334-e0f6617380b7","slug":"ferroptosis","display_name":"Ferroptosis","entity_type_key":"cellular_process"},"role":"object","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""}]},"contexts":[{"dimension":"cell_type","value_text":"Knock-in tissues and derived/engineered cells","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Gpx4 Sec-to-Cys knock-in mice, tissue assays and cell peroxide challenges","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Tissue PCOOH activity was undetectable in reported brain/kidney assays; mutation is not nutritional deficiency.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"organism","value_text":"Mus musculus","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"c76e0bb1-506a-5399-8c8b-b22aee5e0111","evidence_kind":"curated_literature_summary","locator":"lines 1263-1273","start_line":1263,"end_line":1273,"excerpt":"## gpx4-cys-vulnerability\n\nReplacing selenium with sulfur retains some function but weakens peroxide resistance.\n\nGPX4 Sec-to-Cys substitution retains context-dependent residual function but increases peroxide-induced inactivation and ferroptosis susceptibility.\n\nOrganism: Mus musculus\nCell type: Knock-in tissues and derived/engineered cells\nExperimental model: Gpx4 Sec-to-Cys knock-in mice, tissue assays and cell peroxide challenges\nLimitations: Tissue PCOOH activity was undetectable in reported brain/kidney assays; mutation is not nutritional deficiency.\nPrimary reference: [Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis](https://pubmed.ncbi.nlm.nih.gov/29290465/)","model_system":"Gpx4 Sec-to-Cys knock-in mice, tissue assays and cell peroxide challenges","directness":"author_interpretation","verification_status":"secondary_verified","notes":"Curated summary; inspect the linked primary papers for original methods and results.","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"4f892f13-06ea-5199-a33c-a703f35c80ae","stable_key":"selenium-research-2026-09-17","title":"Selenium: literature corrections and mechanism additions","document_type":"curated_literature_review","citation_label":"Metabolic Ledger literature curation, 17 September 2026; primary papers linked individually","file_path":"","sha256":"0b818b10c1c7120e5caf7f4d4019d7bd025d745692e424f515d3ef903c9ab7f3","revision_id":"80984e03-5f0f-5877-8094-afef7637444e","review_status":"secondary_verified","notes":"Secondary curated summaries of primary experiments, with explicit models and limitations. Not archived primary full text."}}],"relations":[],"conflicts":[],"corrections":[{"id":"d0d0ecfd-2114-515e-8a19-2a3054c6c5a6","title":"GPX4-Cys residual function is not normal enzymatic activity","kind":"qualification","status":"qualified","why":"The mouse paper reports undetectable PCOOH activity in tested tissue extracts; residual viability does not mean works fine or not lost activity.","resolution":"Retain Sec-dependent overoxidation protection but distinguish residual function from wild-type activity and mutation from diet.","created_at":"2026-09-17 07:19:34","record_type":"qualification","display_label":"Source qualification","record_url":"/corrections/d0d0ecfd-2114-515e-8a19-2a3054c6c5a6","literature_review":{"revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1584,"end_line":1589,"papers":[{"paper_key":"ingold-2018","title":"Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis","url":"https://pubmed.ncbi.nlm.nih.gov/29290465/","doi":"10.1016/j.cell.2017.11.048","year":2018,"model":"Gpx4 Sec-to-Cys knock-in mice, tissue assays and cell peroxide challenges","summary":"Cys variant retains residual function but is peroxide-sensitive; not normal activity."}]},"sides":[{"conflict_id":"d0d0ecfd-2114-515e-8a19-2a3054c6c5a6","ordinal":0,"label":"Original preserved statement","revision_id":"1fa1ebde-141f-5d47-8a4f-ba87ff84a6c6","start_line":67,"end_line":67,"quote":"The proof: **U46C knock-in GPX4 mice.** Swap the Sec for Cys — the enzyme still works fine in a test tube — and the animals die of ferroptosis in interneurons. Not from lost activity. From *irreversible self-inactivation* under real peroxide load.","claim_id":null,"source_key":"molecular","source_title":"Selenium: the molecular cascade","claim_ids":[]},{"conflict_id":"d0d0ecfd-2114-515e-8a19-2a3054c6c5a6","ordinal":1,"label":"Literature correction and experimental limits","revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1584,"end_line":1589,"quote":"## GPX4-Cys residual function is not normal enzymatic activity\n\nThe mouse paper reports undetectable PCOOH activity in tested tissue extracts; residual viability does not mean works fine or not lost activity.\n\nRetain Sec-dependent overoxidation protection but distinguish residual function from wild-type activity and mutation from diet.\nPrimary reference: [Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis](https://pubmed.ncbi.nlm.nih.gov/29290465/)","claim_id":null,"source_key":"selenium-research-2026-09-17","source_title":"Selenium: literature corrections and mechanism additions","claim_ids":[]}]}],"research":{"topic":"Selenium scientific audit","plain_language":"Replacing selenium with sulfur retains some function but weakens peroxide resistance.","evidence_scope":"direct_experimental","papers":[{"key":"ingold-2018","title":"Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis","url":"https://pubmed.ncbi.nlm.nih.gov/29290465/","doi":"10.1016/j.cell.2017.11.048","year":2018,"model":"Gpx4 Sec-to-Cys knock-in mice, tissue assays and cell peroxide challenges","summary":"Cys variant retains residual function but is peroxide-sensitive; not normal activity."}]}}