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This study investigated whether the arachidonate 15-lipoxygenase-cytosolic phospholipase A2 group IVC-lysophosphatidylcholine 18:0 (ALOX15-PLA2G4C-LPC18:0) axis contributes to HYP-induced hippocampal ferroptosis and CI. Morris water maze testing, Nissl staining, and NeuN immunofluorescence showed that HYP impaired spatial learning and memory and induced hippocampal neuronal loss in mice. Semi-targeted LC\u2013MS\/MS lipidomics revealed marked phospholipid\/lysophospholipid (PL\/LPL) remodeling, characterized by increased phosphatidylcholine and phosphatidylethanolamine species and decreased lysophosphatidylcholine species, particularly LPC18:0. Ferroptosis-related biochemical assays and transmission electron microscopy further demonstrated glutathione (GSH) depletion, malondialdehyde (MDA) accumulation, glutathione peroxidase 4 (GPX4) downregulation, and mitochondrial abnormalities. GEO dataset analysis, qRT-PCR, and Western blotting identified ALOX15 as a HYP-responsive ferroptosis-associated regulator. Hippocampal AAV-mediated Alox15 knockdown improved cognitive performance, preserved hippocampal neurons, suppressed lipid peroxidation, and partially restored PL\/LPL homeostasis. In HYP-exposed SH-SY5Y cells, genetic and pharmacological experiments further supported the contribution of ALOX15 to ferroptosis-related injury. RNA sequencing, promoter-reporter assays, and gain- and loss-of-function experiments suggested that ALOX15 suppressed PLA2G4C expression partly through MAFK-dependent transcriptional modulation. PLA2G4C restoration increased LPC18:0 production, whereas LPC18:0 supplementation attenuated ferroptosis-related injury and improved hippocampal pathology and cognitive performance in HYP-exposed mice. Collectively, these findings support the ALOX15-PLA2G4C-LPC18:0 axis as a potential lipid-remodeling mechanism underlying HYP-induced hippocampal ferroptosis and highlight ALOX15 inhibition and LPC18:0 restoration as potential strategies for mitigating HYP-induced CI.<\/jats:p>","DOI":"10.1186\/s43556-026-00546-w","type":"journal-article","created":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T09:13:39Z","timestamp":1787735619000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Silencing arachidonate 15-lipoxygenase alleviates hypoxia-induced cognitive impairment through the mediation of phospholipase A2 group IVC\u2013LPC18:0 to suppress ferroptosis"],"prefix":"10.1186","volume":"7","author":[{"given":"Zhen","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jutaek","family":"Nam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongchang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,26]]},"reference":[{"issue":"9","key":"546_CR1","doi-asserted-by":"publisher","first-page":"3549","DOI":"10.1073\/pnas.1214912110","volume":"110","author":"F Hyder","year":"2013","unstructured":"Hyder F, Rothman DL, Bennett MR. 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