2. Academic Validation
  3. Ubiquitin Specific Protease 9X Regulates the Activation of ARK5 and Promotes Progression of Fibrotic Remodeling

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

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: guoxiaopenghe@163.com.
  • 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: ymwei12@163.com.
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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