Silencing arachidonate 15-lipoxygenase alleviates hypoxia-induced cognitive impairment through the mediation of phospholipase A2 group IVC–LPC18:0 to suppress ferroptosis

Hypoxic injury is a major contributor to cognitive impairment (CI), but the lipid metabolic mechanisms linking hypoxia (HYP) to hippocampal ferroptosis remain understood. 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-MS/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.