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 d...
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BMC
2024-12-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | https://doi.org/10.1186/s12964-024-01955-6 |
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| author | Xiaowen Shi Jianjiang Xu Xin Zhong Yuanyuan Qian Liming Lin Zimin Fang Bozhi Ye Yiting Lyu Ran Zhang Zhanxiong Zheng Jibo Han |
| author_facet | Xiaowen Shi Jianjiang Xu Xin Zhong Yuanyuan Qian Liming Lin Zimin Fang Bozhi Ye Yiting Lyu Ran Zhang Zhanxiong Zheng Jibo Han |
| author_sort | Xiaowen Shi |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b10407e7045d4f0085441caeb0acc6f5 |
| institution | OA Journals |
| issn | 1478-811X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
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| series | Cell Communication and Signaling |
| spelling | doaj-art-b10407e7045d4f0085441caeb0acc6f52025-08-20T01:57:16ZengBMCCell Communication and Signaling1478-811X2024-12-0122111610.1186/s12964-024-01955-6Deubiquitinase MYSM1 promotes doxorubicin-induced cardiotoxicity by mediating TRIM21-ferroptosis axis in cardiomyocytesXiaowen Shi0Jianjiang Xu1Xin Zhong2Yuanyuan Qian3Liming Lin4Zimin Fang5Bozhi Ye6Yiting Lyu7Ran Zhang8Zhanxiong Zheng9Jibo Han10Department of Cardiology, The Second Affiliated Hospital of Jiaxing UniversityDepartment of Cardiology, The Second Affiliated Hospital of Jiaxing UniversityDepartment of Cardiology, The Second Affiliated Hospital of Jiaxing UniversityKey Laboratory of Blood-stasis-toxin Syndrome of Zhejiang Province, Zhejiang Chinese Medical UniversityDepartment of Cardiology, the First Affiliated Hospital, Wenzhou Medical UniversityDepartment of Ultrasound, Puer People’s HospitalDepartment of Cardiology, the First Affiliated Hospital, Wenzhou Medical UniversityDepartment of Cardiology, The Second Affiliated Hospital of Jiaxing UniversityDepartment of Cardiology, The Second Affiliated Hospital of Jiaxing UniversityDepartment of Cardiology, The Second Affiliated Hospital of Jiaxing UniversityDepartment of Cardiology, The Second Affiliated Hospital of Jiaxing UniversityAbstract 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.https://doi.org/10.1186/s12964-024-01955-6DoxorubicinCardiotoxicityDeubiquitinating enzymesMYSM1TRIM21Ferroptosis |
| spellingShingle | Xiaowen Shi Jianjiang Xu Xin Zhong Yuanyuan Qian Liming Lin Zimin Fang Bozhi Ye Yiting Lyu Ran Zhang Zhanxiong Zheng Jibo Han Deubiquitinase MYSM1 promotes doxorubicin-induced cardiotoxicity by mediating TRIM21-ferroptosis axis in cardiomyocytes Cell Communication and Signaling Doxorubicin Cardiotoxicity Deubiquitinating enzymes MYSM1 TRIM21 Ferroptosis |
| title | Deubiquitinase MYSM1 promotes doxorubicin-induced cardiotoxicity by mediating TRIM21-ferroptosis axis in cardiomyocytes |
| title_full | Deubiquitinase MYSM1 promotes doxorubicin-induced cardiotoxicity by mediating TRIM21-ferroptosis axis in cardiomyocytes |
| title_fullStr | Deubiquitinase MYSM1 promotes doxorubicin-induced cardiotoxicity by mediating TRIM21-ferroptosis axis in cardiomyocytes |
| title_full_unstemmed | Deubiquitinase MYSM1 promotes doxorubicin-induced cardiotoxicity by mediating TRIM21-ferroptosis axis in cardiomyocytes |
| title_short | Deubiquitinase MYSM1 promotes doxorubicin-induced cardiotoxicity by mediating TRIM21-ferroptosis axis in cardiomyocytes |
| title_sort | deubiquitinase mysm1 promotes doxorubicin induced cardiotoxicity by mediating trim21 ferroptosis axis in cardiomyocytes |
| topic | Doxorubicin Cardiotoxicity Deubiquitinating enzymes MYSM1 TRIM21 Ferroptosis |
| url | https://doi.org/10.1186/s12964-024-01955-6 |
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