Deubiquitinase USP25 Alleviates Obesity- Induced Cardiac Remodeling and Dysfunction by Downregulating TAK1 and Reducing TAK1-Mediated Inflammation

Deubiquitinating enzymes play a vital role in cardiovascular diseases. This study found that cardiomyocyte ubiquitin-specific protease 25 (USP25) expression was downregulated both in myocardial tissue of obesity cardiomyopathy and palmitic acid-stimulated cardiomyocytes. USP25 deficiency exacerbated high-fat diet- induced ventricular remodeling in mice, whereas overexpression of USP25 in cardiomyocytes reversed this pathological phenotype. Mechanistically, USP25 directly binds to TAI<1 and P62, and the 178-cysteine of USP25 removes the I<63 ubiquitin chain from P62, which promotes the degradation of TAI<1 through the autophagylysosome pathway, thereby ameliorating obesity-induced ventricular remodeling by reducing inflammation through the TAI<1-MAPI< pathway. This finding identifies USP25 as a potential therapeutic target for obesity cardiomyopathy. (JACC Basic TranslSci. 2024;9:1287-1304) (c) 2024 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC- ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).