Ubiquitin Specific Protease 9X Regulates the Activation of ARK5 and Promotes Progression of Fibrotic Remodeling

  • JACC Basic Transl Sci. 2025 Apr 30:101255. doi: 10.1016/j.jacbts.2025.02.014.
Xuelian Li  1 ,  Shijiu Jiang  1 ,  Wenling Yang  1 ,  Xianjie Zhu  2 ,  Fan Zhang  1 ,  Zhiyang Li  1 ,  Xiaopeng Guo  3 ,  Yumiao Wei  4
Affiliations
  • 1. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 2. Department of Orthopedics, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China; Graduate School of Dalian Medical University, Dalian, China.
  • 3. Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address: [email protected].
  • 4. Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Electronic address: [email protected].
PMID: 40310323 DOI: 10.1016/j.jacbts.2025.02.014
Abstract

USP9X plays a crucial role in myocardial fibrosis. This study showed increased USP9X expression in myocardial infarction models, associated with Collagen deposition and myofibroblast activation. Myofibroblast-specific USP9X knockout and pharmacologic inhibition with Degrasyn both reduced fibrosis and improved cardiac function. Mechanistically, USP9X was found to bind and deubiquitinate AMPK-related kinase 5, thereby activating it and promoting transforming growth factor-β1-induced myofibroblast transformation via the Rho kinase pathway. These findings highlight USP9X as a potential therapeutic target for fibrotic diseases.

Keywords
ARK5; USP9X; cardiac fibrosis; myocardial infarction; myofibroblast transformation.
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