Cardiomyocyte-derived USP13 protects hearts from hypertrophy via deubiquitinating and stabilizing STAT1 in male mice

Jibo Han, Liming Lin, Zimin Fang, Diyun Xu, Lintao Wang, Bozhi Ye, Xue Han, Xiaohong Long, Julian Min, Gaojun Wu, Guang Liang () and Yi Wang ()
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Jibo Han: the First Affiliated Hospital of Wenzhou Medical University
Liming Lin: Wenzhou Medical University
Zimin Fang: the First Affiliated Hospital of Wenzhou Medical University
Diyun Xu: the First Affiliated Hospital of Wenzhou Medical University
Lintao Wang: Nanjing University
Bozhi Ye: the First Affiliated Hospital of Wenzhou Medical University
Xue Han: Hangzhou Medical College
Xiaohong Long: Nanjing University
Julian Min: Hangzhou Medical College
Gaojun Wu: the First Affiliated Hospital of Wenzhou Medical University
Guang Liang: the First Affiliated Hospital of Wenzhou Medical University
Yi Wang: the First Affiliated Hospital of Wenzhou Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Cardiac hypertrophy leads to ventricular dysfunction and heart failure. Deubiquitinating enzymes are responsible for preserving the substrate protein stability and are essential to myocardial hypertrophy. In this study, we aimed to explore the role and regulatory mechanism of a cardiomyocyte-derived deubiquitinating enzyme, USP13, in cardiac hypertrophy. Here we show that USP13 was increased in hypertrophic myocardium and was mainly distributed in cardiomyocytes. Cardiomyocyte-specific Usp13 knockout aggravated TAC or Ang II-induced myocardial hypertrophy and dysfunction in male mice. Correspondingly, USP13 overexpression by AAV9 in hearts exerted a therapeutic impact on cardiac hypertrophy in male mice. Mechanistically, we identified STAT1 as a substrate of USP13 through interactome analysis. USP13 deubiquitinated STAT1, thereby reducing its degradation. Subsequently, USP13 promoted the STAT1-targeted Nppb gene transcription and enhanced mitochondrial function in cardiomyocytes. This study illustrated a beneficial effect of USP13 in hypertrophic cardiomyocytes and identified a cardiomyocyte-specific USP13-STAT1 axis in regulating cardiac hypertrophy.

Date: 2025
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DOI: 10.1038/s41467-025-61028-1

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