CYP2U1: a cardiac metabolic switch alleviating obesity cardiomyopathy via lipid metabolic reprogramming.

Cytochrome P450 2U1 (CYP2U1) modulates lipid metabolism, yet its role in obesity-induced cardiomyopathy remains unknown. Here, we demonstrate that cardiac-specific overexpression of CYP2U1 safeguards against high-fat diet (HFD)-induced myocardial dysfunction. Mice received tail-vein injection of adeno-associated virus serotype 9 (AAV9) carrying CYP2U1 under the cardiac troponin T promoter (AAV9-cTnT-CYP2U1) and were maintained on a 16-week HFD. Cardiac-specific CYP2U1 overexpression was associated with better preservation of systolic function and with reduced myocardial hypertrophy, interstitial fibrosis, and cardiac inflammation. By combining transcriptomics, untargeted metabolomics, and oxylipidomics, we identified two protective mechanisms. Transcriptomic analysis indicated that CYP2U1 attenuated multiple inflammatory cascades, including nuclear factor-κB (NF-κB) p65 phosphorylation and nuclear translocation, with a corresponding reduction in interleukin-6 (IL-6) transcription; CCAAT/enhancer-binding protein β (C/EBPβ) may contribute to this regulation. Metabolomic analysis suggested that CYP2U1 remodels polyunsaturated fatty acid metabolism, consistent with a "metabolic switch" that shifts the balance away from pro-inflammatory arachidonic acid-derived hydroxyeicosatetraenoic acids (HETEs) toward the docosahexaenoic acid (DHA) pathway, with increased levels of the protective lipid mediators 19,20-epoxydocosapentaenoic acid (19,20-EDP) and protectin DX (PDX). In vitro, CYP2U1 overexpression in palmitic acid-challenged H9C2 cells reproduced these anti-inflammatory and metabolic features. CYP2U1 therefore limits obesity-driven cardiac inflammation by coupling suppression of the NF-κB/C/EBPβ-IL-6 axis with a shift in lipid mediators toward DHA-derived specialized pro-resolving mediators. Whether targeted activation of CYP2U1 can be translated into a therapeutic strategy for obesity-associated cardiomyopathy warrants further investigation.