Diabetic cardiomyopathy (DCM) is a leading cause of diabetes-related mortality. Identifying new functional proteins in DCM pathology and elucidating the underlying mechanisms may provide new therapeutic targets for this disease. Here, we observed that the expression of the deubiquitinating enzyme USP13 was significantly downregulated in DCM mouse heart tissues. We discovered that the expression of USP13 was predominantly localized in cardiomyocytes. Cardiomyocyte-specific knockout of USP13 exacerbated myocardial injury in both type I and type II diabetic mice. Conversely, overexpression of USP13 in cardiomyocytes via recombinant adeno-associated virus 9 (AAV9) showed therapeutic effects against DCM in mice. Interestingly, using co-precipitation and LC-MS/MS analysis, we identified the NOD-like receptor family pyrin domain containing 3 (NLRP3) as a target protein of USP13 in cardiomyocytes. Mechanistically, we have illustrated that USP13 removes the K63-linked ubiquitin chain at K557 of NLRP3 to inhibit NLRP3-ASC interaction, thereby inhibiting ASC polymerization and the activation of NLRP3 inflammasome complex, ultimately alleviating pyroptosis in HG + PA challenged cardiomyocytes. Importantly, we showed that the cardioprotective effects of USP13 overexpression depended on NLRP3, as evidenced by the loss of protection in NLRP3-deficient diabetic mice. Taken together, this study identifies the protective impact and molecular regulation of USP13 in DCM pathology, uncovering a novel cardiomyocyte-specific USP13-NLRP3 axis in DCM.
© 2025. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.