Docosapentaenoic Acid n-6 Suppresses Macrophage Ferroptosis in Sepsis-Induced Acute Liver Injury by Targeting the ALOX15/PEBP1 Complex

Abstract Sepsis-induced acute liver injury (SALI) is a major cause of mortality in sepsis, while effective targeted therapies remain limited. Ferroptosis has emerged as a critical mechanism contributing to septic organ damage; however, endogenous regulators of this process remain poorly understood. Here, we identify docosapentaenoic acid n-6 (DPAn-6), a downstream metabolite of dietary linoleic acid (LA), as a potent endogenous inhibitor of macrophage ferroptosis during SALI. Untargeted lipid metabolomics revealed that DPAn-6 was markedly increased following LA supplementation. Administration of DPAn-6 significantly improved survival, alleviated hepatic injury, suppressed inflammatory responses, and reduced ferroptotic features in septic mice, with superior protective effects compared with docosahexaenoic acid. Mechanistically, DPAn-6 directly interacted with arachidonate 15-lipoxygenase (ALOX15) and disrupted the formation of the pro-ferroptotic ALOX15/PEBP1 complex, thereby reducing lipid peroxidation, restoring GPX4 activity, and preserving mitochondrial integrity in macrophages. Structural analysis identified Glu650 of ALOX15 as a critical residue mediating DPAn-6 binding and functional regulation. Mutation of this residue abolished the anti-ferroptotic and hepatoprotective effects of DPAn-6 in vitro and in vivo. Collectively, our findings establish DPAn-6 as a previously unrecognized regulator of ferroptosis and reveal the LA-DPAn-6-ALOX15 axis as a promising therapeutic target for sepsis-induced liver injury.