2. Academic Validation
  3. Tripartite motif 25 ameliorates doxorubicin-induced cardiotoxicity by degrading p85α

Tripartite motif 25 ameliorates doxorubicin-induced cardiotoxicity by degrading p85α

  • Cell Death Dis. 2022 Jul 23;13(7):643. doi: 10.1038/s41419-022-05100-4.
Yihui Shen  # 1 2,  Hui Zhang  # 1 2,  Yangyue Ni  # 3,  Xuejun Wang 1 2,  Yifan Chen 2,  Jiahui Chen 2,  Yan Wang 4,  Jinyi Lin 2,  Yuchen Xu 2,  Jian-Yuan Zhao 5,  Leilei Cheng 6 7
Affiliations

Affiliations

  • 1 Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai Institute of Medical Imaging, 180 Fenglin Road, Shanghai, China.
  • 2 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, China.
  • 3 State Key Laboratory of Cell Biology, Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, China.
  • 4 Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 5 Institute for Developmental and Regenerative Cardiovascular Medicine, MOE-Shanghai Key Laboratory of Children's Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China. zhaojy@vip.163.com.
  • 6 Department of Echocardiography, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai Institute of Medical Imaging, 180 Fenglin Road, Shanghai, China. cheng.leilei@zs-hospital.sh.cn.
  • 7 Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, China. cheng.leilei@zs-hospital.sh.cn.
  • # Contributed equally.
PMID: 35871160 DOI: 10.1038/s41419-022-05100-4
Abstract

Doxorubicin (DOX)-based chemotherapy is widely used to treat malignant tumors; however, the cardiotoxicity induced by DOX restricts its clinical usage. A therapeutic dose of DOX can activate ubiquitin-proteasome system. However, whether and how ubiquitin-proteasome system brings out DOX-induced cardiotoxicity remains to be investigated. Here we conducted a proteomics analysis of a DOX-induced cardiotoxicity model to screen the potentially ubiquitination-related molecules. Dysregulated TRIM25 was found to contribute to the cardiotoxicity. In vivo and in vitro cardiotoxicity experiments revealed that TRIM25 ameliorated DOX-induced cardiotoxicity. Electron microscopy and endoplasmic reticulum stress markers revealed that TRIM25 mitigated endoplasmic reticulum stress and Apoptosis in DOX-induced cardiomyocytes. Mechanistically, the Co-immunoprecipitation assays and CHX pulse-chase experiment determined that TRIM25 affected p85α stability and promoted its ubiquitination and degradation. This leads to increase of nuclear translocation of XBP-1s, which mitigates endoplasmic reticulum stress. These findings reveal that TRIM25 may have a therapeutic role for DOX-induced cardiotoxicity.

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