SIRT5 Inhibits HMGCS2 Succinylation and Promotes Its PIAS4‐Dependent Ubiquitination to Attenuate Diabetic Cardiomyopathy

ABSTRACT Diabetic cardiomyopathy (DCM) is characterized by metabolic dysregulation and progressive cardiac dysfunction, but the underlying molecular mechanisms remain incompletely understood. Emerging evidence suggests that 3‐hydroxy‐3‐methylglutaryl‐CoA synthase 2 (HMGCS2) may play an important role in DCM pathogenesis. This study reveals a novel regulatory mechanism involving SIRT5‐mediated post‐translational modification of HMGCS2 in DCM pathogenesis using high glucose‐treated cardiomyocyte models and DCM mouse models. In DCM models, HMGCS2 was significantly upregulated and found to promote cardiomyocyte pyroptosis, cardiac dysfunction, and myocardial tissue damage. In contrast, SIRT5 exhibited cardioprotective effects under the same conditions. Moreover, SIRT5 overexpression reduced HMGCS2 succinylation while enhancing its ubiquitination and degradation in cardiomyocytes under high glucose conditions. Mechanistically, SIRT5 facilitated ubiquitin‐mediated degradation of HMGCS2 at K118 by upregulating the E3 ubiquitin ligase PIAS4. In conclusion, SIRT5 mediated HMGCS2 desuccinylation while promoting PIAS4‐dependent HMGCS2 ubiquitination and degradation. This study identified the SIRT5/PIAS4/HMGCS2 axis as a critical regulatory pathway in DCM, suggesting that targeting SIRT5 to influence HMGCS2 post‐translational modifications might offer a novel therapeutic approach for DCM.