2. Academic Validation
  3. Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin

Loss of TRIM21 alleviates cardiotoxicity by suppressing ferroptosis induced by the chemotherapeutic agent doxorubicin

  • EBioMedicine. 2021 Jul;69:103456. doi: 10.1016/j.ebiom.2021.103456.
Kai Hou 1,  Jianliang Shen 2,  Junrong Yan 2,  Chuannan Zhai 3,  Jingxia Zhang 4,  Ji-An Pan 5,  Ye Zhang 6,  Yaping Jiang 7,  Yongbo Wang 8,  Richard Z Lin 7,  Hongliang Cong 9,  Shenglan Gao 10,  Wei-Xing Zong 11
Affiliations

Affiliations

  • 1 School of Medicine, Nankai University, Tianjin, China; Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China; Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA; Department of Cardiology, Tianjin Chest Hospital, Tianjin, China.
  • 2 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA.
  • 3 School of Medicine, Nankai University, Tianjin, China; Department of Cardiology, Tianjin Chest Hospital, Tianjin, China.
  • 4 Department of Cardiology, Tianjin Chest Hospital, Tianjin, China.
  • 5 Department of Biochemistry and Molecular Cell Biology, School of Medicine, Sun Yat-sen University, Shenzhen, China.
  • 6 Tianjin Third Central Hospital, Tianjin, China.
  • 7 Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, USA.
  • 8 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 9 School of Medicine, Nankai University, Tianjin, China; Department of Cardiology, Tianjin Chest Hospital, Tianjin, China. Electronic address: hongliangcong@163.com.
  • 10 Department of Cellular and Genetic Medicine, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: sgao@fudan.edu.cn.
  • 11 Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA. Electronic address: zongwx@rutgers.edu.
PMID: 34233258 DOI: 10.1016/j.ebiom.2021.103456
Abstract

Background: Doxorubicin, an anthracycline chemotherapeutic agent, is widely used in the treatment of many cancers. However, doxorubicin posts a great risk of adverse cardiovascular events, which are thought to be caused by oxidative stress. We recently reported that the ubiquitin E3 Ligase TRIM21 interacts and ubiquitylates p62 and negatively regulates the p62-Keap1-Nrf2 antioxidant pathway. Therefore, we sought to determine the role TRIM21 in cardiotoxicity induced by oxidative damage.

Methods: Using TRIM21 knockout mice, we examined the effects of TRIM21 on cardiotoxicity induced by two oxidative damage models: the doxorubicin treatment model and the Left Anterior Descending (LAD) model. We also explored the underlying mechanism by RNA-sequencing of the heart tissues, and by treating the mouse embryonic fibroblasts (MEFs), immortalized rat cardiomyocyte line H9c2, and immortalized human cardiomyocyte line AC16 with doxorubicin.

Findings: TRIM21 knockout mice are protected from heart failure and fatality in both the doxorubicin and LAD models. Hearts of doxorubicin-treated wild-type mice exhibit deformed mitochondria and elevated level of lipid peroxidation reminiscent of Ferroptosis, which is alleviated in TRIM21 knockout hearts. Mechanistically, TRIM21-deficient heart tissues and cultured MEFs and H9c2 cells display enhanced p62 sequestration of Keap1 and are protected from doxorubicin-induced Ferroptosis. Reconstitution of wild-type but not the E3 ligase-dead and the p62 binding-deficient TRIM21 mutants impedes the protection from doxorubicin-induced cell death.

Interpretation: Our study demonstrates that TRIM21 ablation protects doxorubicin-induced cardiotoxicity and illustrates a new function of TRIM21 in Ferroptosis, and suggests TRIM21 as a therapeutic target for reducing chemotherapy-related cardiotoxicity.

Funding: NIH (CA129536; DK108989): data collection, analysis. Shanghai Pujiang Program (19PJ1401900): data collection. National Natural Science Foundation (31971161): data collection. Department of Veteran Affairs (BX004083): data collection. Tianjin Science and Technology Plan Project (17ZXMFSY00020): data collection.

Keywords

Antioxidant; Cardiotoxicity; Doxorubicin; Ferroptosis; TRIM21.

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