UBE2I Alleviates Pyroptosis in Coronary Heart Disease by Promoting the SUMOylation and Degradation of NLRP3

OBJECTIVE: Coronary heart disease (CHD), a major cardiovascular disorder, involves myocardial injury, inflammation, and fibrosis. NLRP3 inflammasome-driven pyroptosis plays a critical role in CHD progression. Although the ubiquitin-conjugating enzyme E2I (UBE2I) regulates protein SUMOylation, its function in CHD remains poorly understood. This study explores the expression and role of UBE2I in CHD, specifically examining its potential to mitigate myocardial injury and fibrosis via regulation of NLRP3 SUMOylation and pyroptosis. METHODS: mice fed a high-fat diet, followed by lentivirus-mediated UBE2I overexpression. In vitro, ox-LDL-induced H9C2 cardiomyocytes were transfected with UBE2I overexpression or knockdown plasmids. Cardiac function, fibrosis, inflammatory cytokines, and pyroptosis were assessed via echocardiography, Masson staining, ELISA, flow cytometry, qPCR, and immunoblotting. Protein interactions and SUMOylation were evaluated using co-immunoprecipitation and site-directed mutagenesis. RESULTS: UBE2I expression was significantly downregulated in CHD mice and ox-LDL-induced H9C2 cells. Overexpression of UBE2I improved cardiac function, reduced myocardial injury markers, attenuated fibrosis, and decreased levels of pro-inflammatory cytokines. It also suppressed NLRP3-mediated pyroptosis. Mechanistically, UBE2I promoted SUMOylation of NLRP3 at lysine 202, leading to its destabilization and degradation. Overexpression of NLRP3 reversed the protective effects of UBE2I in vitro. CONCLUSIONS: This study provided a new perspective for the treatment of CHD, that is, UBE2I accelerated the degradation of NLRP3 through the SUMOylation pathway, thereby exerting an anti-pyroptosis effect. Therefore, UBE2I was a promising therapeutic target for CHD.