Decreased 13-HODE as a metabolic signature of enhanced lipid peroxidation in hypertriglyceridemic pancreatitis

The global incidence of hypertriglyceridemic pancreatitis (HTGP) is increasing, particularly in China, highlighting the urgent need to understand its pathogenesis. Given the metabolic basis of HTGP, this study aimed to define its specific metabolic profile and identify potential therapeutic targets. We first performed plasma metabolomic analysis in patients with acute pancreatitis of different etiologies, identifying a distinct HTGP signature characterized by significant reduction in 13-hydroxyoctadecadienoic acid (13-HODE) levels, which was validated in an HTGP rat model. Decreased 13-HODE reflects redirected metabolic flux along the ALOX15 lipid peroxidation cascade and metabolic reprogramming. We therefore employed oxidized lipidomics and confirmed the accumulation of oxidized lipids. Notably, specific phosphatidylethanolamine hydroperoxide (PE-OOH) was detected in both systemic circulation and pancreatic tissue, and the levels of PE-OOH were positively correlated with disease severity. Considering the central role of lipid peroxidation, we focused on arachidonate 15-lipoxygenase (ALOX15), a key enzyme in this pathway. Treatment with two different ALOX15 inhibitors, PD146176 and baicalein, effectively alleviated disease phenotype and reduced lipid peroxidation in HTGP. Taken together, our findings establish a correlation between decreased 13-HODE and enhanced lipid peroxidation in HTGP and demonstrate that ALOX15 inhibition represents a promising therapeutic strategy.