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

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.