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

Overview

Journal JACC Basic Transl Sci

Date 2024 Dec 2

PMID 39619140

Authors

Bozhi Ye

Yanghao Chen

Xudong Chen

Diyun Xu

Yucheng Jiang

Wante Lin

Danhong Fang

Jiachen Xu

Jibo Han

Xue Han

Xiaohong Long

Wei Wang

Hao Zhou

Gaojun Wu

Guang Liang

Affiliations

Soon will be listed here.

Abstract

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 TAK1 and P62, and the 178-cysteine of USP25 removes the K63 ubiquitin chain from P62, which promotes the degradation of TAK1 through the autophagy-lysosome pathway, thereby ameliorating obesity-induced ventricular remodeling by reducing inflammation through the TAK1-MAPK pathway. This finding identifies USP25 as a potential therapeutic target for obesity cardiomyopathy.

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