Deubiquitinase MYSM1 promotes doxorubicin-induced cardiotoxicity by mediating TRIM21-ferroptosis axis in cardiomyocytes.

Abstract

Anthracycline antitumor drug doxorubicin (DOX) induces severe cardiotoxicity. Deubiquitinating enzymes (DUBs) are crucial for protein stability and function and play a significant role in cardiac pathophysiology. By comparing RNA sequencing datasets and conducting functional screening, we determined that Myb-like, SWIRM, and MPN domains 1 (MYSM1) is a key regulator of DOX-induced cardiotoxicity. In this study, we aimed to explore the function and regulatory mechanisms of MYSM1 in DOX-induced cardiotoxicity. Genetic knockdown of MYSM1 significantly mitigated DOX-induced cardiomyopathy. Correspondingly, cardiomyocyte-specific knockdown of MYSM1 by AAV9 protected the heart from DOX-induced cardiotoxicity. Gain- and loss-of-function analysis verified that MYSM1 mediated DOX-induced cardiomyocyte injury in vitro. Through a Co-IP combined with LC-MS/MS analysis, we discovered that MYSM1 directly interacted with tripartite motif-containing protein 21 (TRIM21). Mechanistic investigations revealed that MYSM1 regulates the deubiquitination and the stability of TRIM21 via its MPN domain. Furthermore, MYSM1 exacerbated DOX-induced cardiotoxicity by enhancing ferroptosis. This study identified MYSM1 as a potential therapeutic target for DOX-induced cardiotoxicity and illustrated a MYSM1-TRIM21-ferroptosis axis in regulating DOX-induced cardiotoxicity.