Inhibition of the CYP2E1-19-HETE-BLT2-mediated oxidative injury amplification by FGF21 alleviates myocardial infarction remodeling.

The arachidonic acid (AA) metabolic cascade plays important roles across multiple pathological conditions; however, the contribution of AA-derived lipid metabolism to myocardial infarction (MI) remains incompletely understood. Here, we combined targeted oxylipidomics, experimental and clinical MI analyses, transcriptomic integration, and mechanistic studies to investigate cytochrome P450-2E1 (CYP2E1)-associated metabolic remodeling during MI. Oxylipidomic profiling identified 19-hydroxyeicosatetraenoic acid (19-HETE) as a prominently elevated AA-derived metabolite in experimental MI and linked to impaired cardiac function in clinical MI. Mechanistically, we found that exogenous 19-HETE aggravated oxidative stress and apoptosis in cardiomyocytes, whereas pharmacological inhibition of leukotriene B4 receptor 2 (BLT2) partially attenuated these effects, supporting BLT2-related signaling involvement. CYP2E1 inhibition reduced circulating 19-HETE levels and alleviated myocardial injury. Integrative transcriptomic and experimental analyses further identified fibroblast growth factor 21 (FGF21) as an upstream regulator associated with CYP2E1-related oxidative metabolism. FGF21 deficiency aggravated CYP2E1-associated metabolic remodeling after MI, whereas FGF21 restoration suppressed CYP2E1 expression and 19-HETE accumulation through activation of sirtuin 1 (Sirt1). Moreover, we found that Sacubitril/Valsartan attenuated CYP2E1-associated metabolic remodeling in an FGF21-dependent manner. These findings support CYP2E1-associated lipid metabolic remodeling as a contributor to oxidative injury during MI and suggest a potential therapeutic relevance of targeting this pathway.