{"id":"b24ff4df-02a6-5e9f-8b8f-a873513161f3","stable_key":"research:acsl4-activation","predicate":"produces","statement":"ACSL4 activates arachidonic acid to arachidonoyl-CoA upstream of phospholipid incorporation.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"literature_reviewed:direct_experimental","direction":"positive","is_public":true,"mechanism_event_id":"b85b11a2-898d-59f8-b137-f4177ea4577b","mechanism_event_label":"ACSL4 prepares the fatty acid for membrane incorporation.","subject":{"id":"292e42f2-e14f-5b59-90c1-0d2cb1e3ba2d","slug":"acsl4","display_name":"ACSL4","entity_type_key":"protein"},"object":{"id":"d57c5904-b492-5a04-9162-429f368fafd2","slug":"arachidonoyl-coa","display_name":"arachidonoyl-CoA","entity_type_key":"small_molecule"},"evidence_count":1,"mechanism_event":{"id":"b85b11a2-898d-59f8-b137-f4177ea4577b","stable_key":"research:acsl4-activation","event_type":"fatty_acid_activation","label":"ACSL4 prepares the fatty acid for membrane incorporation.","description":"ACSL4 activates arachidonic acid to arachidonoyl-CoA upstream of phospholipid incorporation.","status":"active","compartment":null,"participants":[{"entity":{"id":"39f9446f-52a6-502d-b507-91137726f82c","slug":"arachidonic-acid","display_name":"AA","entity_type_key":"small_molecule"},"role":"substrate","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"292e42f2-e14f-5b59-90c1-0d2cb1e3ba2d","slug":"acsl4","display_name":"ACSL4","entity_type_key":"protein"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"d57c5904-b492-5a04-9162-429f368fafd2","slug":"arachidonoyl-coa","display_name":"arachidonoyl-CoA","entity_type_key":"small_molecule"},"role":"object","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""}]},"contexts":[{"dimension":"cell_type","value_text":"Experimental cell models","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"Not proof of ACSL4 dependence in every ferroptosis model.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"organism","value_text":"Mus musculus","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"27ef4e6a-2555-5fc2-9ca4-40551f23b847","evidence_kind":"curated_literature_summary","locator":"lines 1215-1225","start_line":1215,"end_line":1225,"excerpt":"## acsl4-activation\n\nACSL4 prepares the fatty acid for membrane incorporation.\n\nACSL4 activates arachidonic acid to arachidonoyl-CoA upstream of phospholipid incorporation.\n\nOrganism: Mus musculus\nCell type: Experimental cell models\nExperimental model: Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics\nLimitations: Not proof of ACSL4 dependence in every ferroptosis model.\nPrimary reference: [Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis](https://pubmed.ncbi.nlm.nih.gov/27842066/)","model_system":"Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics","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":"d47d5b8e-8380-5767-9b01-f7c4b1f02f64","title":"ACSL4 activation precedes LPCAT3-mediated lipid incorporation","kind":"contradiction","status":"corrected","why":"Initial diagram places PE esterification before LPCAT3; the second source already supplies the correct sequence.","resolution":"Preserve both diagrams and separate AA to AA-CoA to PE-AA steps.","created_at":"2026-09-17 07:19:34","record_type":"correction","display_label":"Correction history","record_url":"/corrections/d47d5b8e-8380-5767-9b01-f7c4b1f02f64","literature_review":{"revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1563,"end_line":1568,"papers":[{"paper_key":"kagan-2017","title":"Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis","url":"https://pubmed.ncbi.nlm.nih.gov/27842066/","doi":"10.1038/nchembio.2238","year":2017,"model":"Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics","summary":"ACSL4 activation precedes LPCAT3-mediated phospholipid incorporation."}]},"sides":[{"conflict_id":"d47d5b8e-8380-5767-9b01-f7c4b1f02f64","ordinal":0,"label":"Original preserved statement","revision_id":"1fa1ebde-141f-5d47-8a4f-ba87ff84a6c6","start_line":91,"end_line":91,"quote":"PUFA (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":"d47d5b8e-8380-5767-9b01-f7c4b1f02f64","ordinal":1,"label":"Original preserved statement","revision_id":"4cec6304-35d7-5560-9133-e6ea689db838","start_line":111,"end_line":111,"quote":"AA ──ACSL4──► AA-CoA ──LPCAT3──► PE-AA ──ALOX15/PEBP1──► PE-AA-OOH","claim_id":null,"source_key":"corrections","source_title":"Selenium corrections and deep dive","claim_ids":[]},{"conflict_id":"d47d5b8e-8380-5767-9b01-f7c4b1f02f64","ordinal":2,"label":"Literature correction and experimental limits","revision_id":"80984e03-5f0f-5877-8094-afef7637444e","start_line":1563,"end_line":1568,"quote":"## ACSL4 activation precedes LPCAT3-mediated lipid incorporation\n\nInitial diagram places PE esterification before LPCAT3; the second source already supplies the correct sequence.\n\nPreserve both diagrams and separate AA to AA-CoA to PE-AA steps.\nPrimary reference: [Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis](https://pubmed.ncbi.nlm.nih.gov/27842066/)","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":"ACSL4 prepares the fatty acid for membrane incorporation.","evidence_scope":"direct_experimental","papers":[{"key":"kagan-2017","title":"Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis","url":"https://pubmed.ncbi.nlm.nih.gov/27842066/","doi":"10.1038/nchembio.2238","year":2017,"model":"Cell genetic perturbation, mouse lung epithelial Lpcat3 knockdown, redox lipidomics","summary":"ACSL4 activation precedes LPCAT3-mediated phospholipid incorporation."}]}}