Deubiquitinase MYSM1 drives myocardial ischemia/reperfusion injury by stabilizing STAT1 in cardiomyocytes

<b>Rationale:</b> Myocardial ischemia/reperfusion (I/R) injury leads to irreversible cardiomyocyte death and aggravates myocardial infarction. Deubiquitinating enzymes (DUBs) are essential for maintaining substrate protein stability and functionality, playing significant roles in cardiac pathophysiology. In this study, we aimed to clarify the regulatory role of a DUB, Myb-like, SWIRM, and MPN domains 1 protein (MYSM1), in myocardial I/R injury and explore the molecular mechanism behind. <b>Methods and Results:</b> Firstly, it was found that the expression of MYSM1 positively correlates with myocardial I/R injury. Genetic knockdown of MYSM1 significantly conferred protection against I/R injury in hearts. Correspondingly, AAV9-mediated cardiomyocyte-specific knockdown of MYSM1 had a therapeutic effect on myocardial I/R injury. Through a comprehensive proteome-wide quantitative analysis, we identified signal transducer and activator of transcription 1 (STAT1) as the direct substrate of MYSM1. Mechanistically, MYSM1 mediated the K63-linked deubiquitination and stabilization of STAT1 at position K379 via its MPN metalloprotease domain. Additionally, MYSM1 initiates the expression of necroptosis-related genes by promoting the transcription factor function of STAT1. <b>Conclusion:</b> This study illustrated a MYSM1-STAT1 axis in regulating myocardial I/R injury and identified MYSM1 as a pharmacological target for myocardial I/R injury.