USP7 aggravates diabetic cardiomyopathy by stabilizing Keap1 to govern cardiac oxidative stress and pyroptosis

Background Diabetic cardiomyopathy (DCM) represents one of the most severe cardiac complications arising from diabetes. However, there is a lack of specific treatment strategies for DCM in clinic. As a key deubiquitylation protease, ubiquitin-specific protease 7 (USP7) has been proved to aggravate pathological processes in a variety of cardiovascular diseases. Despite extensive investigation into USP7, its exact contribution to the onset and development of dilated cardiomyopathy, as well as its viability as a target for therapeutic intervention, remains largely undefined. Methods In this study, gene conditional knockout or chemical inhibition techniques were used to silence the function of USP7 in the hearts of diabetic mice. Both neonatal mouse cardiomyocytes (NMCMs) and H9c2 cells were used to detect the molecular mechanisms underlying the effect of USP7 in DCM. Results We demonstrated that USP7 were up-regulated in diabetic hearts and palmitate (PA) treated cells. Silencing USP7 restored cardiac dysfunction, reduced myocardial fibrosis, inflammation and cardiac pyroptosis in diabetic mice. Mechanistically, we found that USP7 stabilized Keap1 through deubiquitinated activity, contributing to Nrf2 inhibition, hence mediated cardiac oxidative stress and pyroptosis and promoted the progress of DCM. Conclusions Our findings indicate that USP7 exacerbates oxidative stress and triggers pyroptotic cell death in cardiomyocytes by reinforcing Keap1 protein stability, suggesting that pharmacological blockade of USP7 may serve as a novel therapeutic strategy for DCM.