Cardiomyocyte-derived USP13 protects hearts from hypertrophy via deubiquitinating and stabilizing STAT1 in male mice
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 cardiomyocyt...
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Nature Portfolio
2025-07-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-61028-1 |
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| author | Jibo Han Liming Lin Zimin Fang Diyun Xu Lintao Wang Bozhi Ye Xue Han Xiaohong Long Julian Min Gaojun Wu Guang Liang Yi Wang |
| author_facet | Jibo Han Liming Lin Zimin Fang Diyun Xu Lintao Wang Bozhi Ye Xue Han Xiaohong Long Julian Min Gaojun Wu Guang Liang Yi Wang |
| author_sort | Jibo Han |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-beb20df1192242cbb92d31bbdc0a5c31 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-beb20df1192242cbb92d31bbdc0a5c312025-08-20T03:03:44ZengNature PortfolioNature Communications2041-17232025-07-0116111610.1038/s41467-025-61028-1Cardiomyocyte-derived USP13 protects hearts from hypertrophy via deubiquitinating and stabilizing STAT1 in male miceJibo Han0Liming Lin1Zimin Fang2Diyun Xu3Lintao Wang4Bozhi Ye5Xue Han6Xiaohong Long7Julian Min8Gaojun Wu9Guang Liang10Yi Wang11Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical UniversityChemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical UniversityDepartment of Cardiology, the First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Cardiology, the First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Cardiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversityDepartment of Cardiology, the First Affiliated Hospital of Wenzhou Medical UniversitySchool of Pharmaceutical Sciences, Hangzhou Medical CollegeDepartment of Cardiology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing UniversitySchool of Pharmaceutical Sciences, Hangzhou Medical CollegeDepartment of Cardiology, the First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Cardiology, the First Affiliated Hospital of Wenzhou Medical UniversityDepartment of Cardiology, the First Affiliated Hospital of Wenzhou Medical UniversityAbstract 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.https://doi.org/10.1038/s41467-025-61028-1 |
| spellingShingle | Jibo Han Liming Lin Zimin Fang Diyun Xu Lintao Wang Bozhi Ye Xue Han Xiaohong Long Julian Min Gaojun Wu Guang Liang Yi Wang Cardiomyocyte-derived USP13 protects hearts from hypertrophy via deubiquitinating and stabilizing STAT1 in male mice Nature Communications |
| title | Cardiomyocyte-derived USP13 protects hearts from hypertrophy via deubiquitinating and stabilizing STAT1 in male mice |
| title_full | Cardiomyocyte-derived USP13 protects hearts from hypertrophy via deubiquitinating and stabilizing STAT1 in male mice |
| title_fullStr | Cardiomyocyte-derived USP13 protects hearts from hypertrophy via deubiquitinating and stabilizing STAT1 in male mice |
| title_full_unstemmed | Cardiomyocyte-derived USP13 protects hearts from hypertrophy via deubiquitinating and stabilizing STAT1 in male mice |
| title_short | Cardiomyocyte-derived USP13 protects hearts from hypertrophy via deubiquitinating and stabilizing STAT1 in male mice |
| title_sort | cardiomyocyte derived usp13 protects hearts from hypertrophy via deubiquitinating and stabilizing stat1 in male mice |
| url | https://doi.org/10.1038/s41467-025-61028-1 |
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