UBE2E2 targets HMGB1 to regulate cardiomyocyte ferroptosis in experimental autoimmune myocarditis mice to exert a protective effect

Autoimmune myocarditis is a potentially life-threatening disease mediated by myocardial immune injury that can evolve into dilated cardiomyopathy and end-stage heart failure. Numerous studies have shown that ferroptosis is involved in the pathogenesis of several cardiovascular diseases, including heart failure, myocardial infarction, and myocardial fibrosis. However, the involvement of ferroptosis in experimental autoimmune myocarditis (EAM) has a mechanism that is still unclear. In this study, we successfully constructed animal and cellular models of EAM and found that ubiquitin-conjugating enzyme E2E2 (UBE2E2) was lowly expressed in EAM, and that cardiomyocyte ferroptosis was involved in the pathological development of EAM; overexpression of UBE2E2 inhibited inflammatory infiltration and ferroptosis of cardiomyocytes in EAM mice, and significantly improved cardiac remodeling and function. In in vitro experiments, UBE2E2 overexpression increased considerably cell proliferation viability, effectively reduced ROS levels in cardiomyocytes, and enhanced mitochondrial number, morphology, and membrane potential changes. Mass spectrometry screened the UBE2E2 ferroptosis-related interacting protein as HMGB1, and UBE2E2 could inhibit the progression of EAM by ubiquitination degradation of HMGB1. In conclusion, our results suggest that UBE2E2 may inhibit ferroptosis in EAM cardiomyocytes by targeting HMGB1, thereby exerting a protective effect on EAM and providing a new potential target for EAM therapy.