Bibliographic Details
| Title: |
Deubiquitinase MYSM1 promotes doxorubicin-induced cardiotoxicity by mediating TRIM21-ferroptosis axis in cardiomyocytes. |
| Authors: |
Shi, Xiaowen1 (AUTHOR), Xu, Jianjiang1 (AUTHOR), Zhong, Xin1 (AUTHOR), Qian, Yuanyuan2 (AUTHOR), Lin, Liming3 (AUTHOR), Fang, Zimin4 (AUTHOR), Ye, Bozhi3 (AUTHOR), Lyu, Yiting1 (AUTHOR), Zhang, Ran1 (AUTHOR), Zheng, Zhanxiong1 (AUTHOR) zhengzhanxiongjx2y@163.com, Han, Jibo1 (AUTHOR) jibohanjx2y@163.com |
| Source: |
Cell Communication & Signaling. 12/18/2024, Vol. 22 Issue 1, p1-16. 16p. |
| Subject Terms: |
*DEUBIQUITINATING enzymes, *CARDIOTOXICITY, *PROTEIN stability, *RNA sequencing, *ANTINEOPLASTIC agents, *DOXORUBICIN |
| 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. [ABSTRACT FROM AUTHOR] |
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