Deubiquitinase USP13 alleviates doxorubicin-induced cardiotoxicity through promoting the autophagy-mediated degradation of STING.
10.1016/j.apsb.2025.03.051
- Author:
Liming LIN
1
;
Jibo HAN
2
;
Diyun XU
1
;
Zimin FANG
1
;
Bozhi YE
1
;
Jinfu QIAN
1
;
Xue HAN
3
;
Julian MIN
4
;
Xiaohong LONG
4
;
Gaojun WU
1
;
Guang LIANG
1
Author Information
1. Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
2. Department of Cardiology, the Second Affiliated Hospital of Jiaxing University, Jiaxing 314001, China.
3. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
4. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 310014, China.
- Publication Type:Journal Article
- Keywords:
Autophagy;
Cardiomyocyte;
Cardiotoxicity;
Deubiquitinating enzyme;
Doxorubicin;
Inflammation;
STING;
USP13
- From:
Acta Pharmaceutica Sinica B
2025;15(5):2545-2558
- CountryChina
- Language:English
-
Abstract:
Doxorubicin (Dox) is an anthracycline drug widely applied in various malignancies. However, the fatal cardiotoxicity induced by Dox limits its clinical application. Post-transcriptional protein modification via ubiquitination/deubiquitination in cardiomyocytes mediates the pathophysiological process in Dox-induced cardiotoxicity (DIC). In this study, we aimed to clarify the regulatory role and mechanism of a deubiquitinating enzyme, ubiquitin-specific peptidase 13 (USP13), in DIC. RNA-seq analysis and experimental examinations identified that cardiomyocyte-derived USP13 positively correlated with DIC. Mice with cardiac-specific deletion of USP13 were subjected to Dox modeling. Adeno-associated virus serotype 9 (AAV9) carrying cTNT promoter was constructed to overexpress USP13 in mouse heart tissues. Cardiomyocyte-specific knockout of USP13 exacerbated DIC, while its overexpression mitigated DIC in mice. Mechanistically, USP13 deubiquitinates the stimulator of interferon genes (STING) and promotes the autolysosome-related degradation of STING, subsequently alleviating cardiomyocyte inflammation and death. Our study suggests that USP13 serves a cardioprotective role in DIC and indicates USP13 as a potential therapeutic target for DIC treatment.
