Abstract

Although extensive clinical and basic research has been conducted on diabetic cardiomyopathy (DbCM), the therapeutic efficacy for this condition remains significantly limited. Ubiquitin‐specific peptidase 20 (USP20), a deubiquitinating enzyme, plays an essential role in regulating protein ubiquitination and modulating various cellular processes. In this study, we aimed to investigate the effect of USP20 on the pathogenesis of DbCM, which may provide a novel therapeutic target for its treatment. The cardiomyocyte‐specific USP20 conditional knockout (USP20CKO) mice were employed in this study. The type 2 diabetes mouse model was established using db/db leptin receptor–deficient mice and high‐fat diet/streptozotocin–induced mice. USP20 expression was downregulated in the myocardium of diabetic mice. Cardiomyocyte‐specific USP20 deficiency aggravated cardiac remodeling and myocardial dysfunction in diabetic mice. LC–MS/MS analysis, along with Co‐IP results, demonstrated the interaction between stimulator of interferon genes (STING) and USP20. In mechanism, USP20 directly binds to STING and promotes its degradation through the autophagy pathway by deubiquitinating p62 via its active site C154, thereby alleviating the myocardial inflammation and improving ventricular remodeling and heart failure induced by diabetes. USP20 directly binds to STING and promotes the degradation of STING through the autophagy pathway by deubiquitinating p62 via its active site C154, thereby alleviating myocardial inflammation and improving ventricular remodeling and heart failure induced by diabetes.