2. Academic Validation
  3. Pharmacological activation of GPX4 ameliorates doxorubicin-induced cardiomyopathy

Pharmacological activation of GPX4 ameliorates doxorubicin-induced cardiomyopathy

  • Redox Biol. 2024 Apr:70:103024. doi: 10.1016/j.redox.2023.103024.
Chuying Huang 1,  Yishan Guo 2,  Tuo Li 3,  Guogen Sun 3,  Jinru Yang 4,  Yuqi Wang 5,  Ying Xiang 3,  Li Wang 3,  Min Jin 4,  Jiao Li 4,  Yong Zhou 6,  Bing Han 5,  Rui Huang 3,  Jiao Qiu 3,  Yong Tan 3,  Jiaxing Hu 3,  Yumiao Wei 7,  Bo Wu 3,  Yong Mao 8,  Lingshan Lei 8,  Xiusheng Song 3,  Shuijie Li 9,  Yongsheng Wang 10,  Tao Zhang 11
Affiliations

Affiliations

  • 1 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Hubei Selenium and Human Health Institute, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, China; Hubei Provincial Key Lab of Selenium Resources and Bioapplications, Enshi, 445000, China. Electronic address: [email protected].
  • 2 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Department of Cardiology, Binzhou Medical University Hospital, Binzhou, 256600, China.
  • 3 Hubei Selenium and Human Health Institute, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, China; Hubei Provincial Key Lab of Selenium Resources and Bioapplications, Enshi, 445000, China.
  • 4 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 5 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
  • 6 Hubei Selenium and Human Health Institute, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, China.
  • 7 Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
  • 8 Wuhan Frasergen Bioinformatics Co. Ltd., Wuhan, 430070, China.
  • 9 State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, 150081, China. Electronic address: [email protected].
  • 10 Division of Thoracic Tumor Multimodality Treatment, Cancer Center, Sichuan University, West China Hospital, Chengdu, 610041, China. Electronic address: [email protected].
  • 11 Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China. Electronic address: [email protected].
PMID: 38232458 DOI: 10.1016/j.redox.2023.103024
Abstract

Due to the cardiotoxicity of doxorubicin (DOX), its clinical application is limited. Lipid peroxidation caused by excessive ferrous iron is believed to be a key molecular mechanism of DOX-induced cardiomyopathy (DIC). Dexrazoxane (DXZ), an iron chelator, is the only drug approved by the FDA for reducing DIC, but it has many side effects and cannot be used as a preventive drug in clinical practice. Single-nucleus RNA Sequencing (snRNA-seq) analysis identified myocardial and epithelial cells that are susceptible to DOX-induced Ferroptosis. The Glutathione Peroxidase 4 (GPX4) activator selenomethione (SeMet) significantly reduced polyunsaturated fatty acids (PUFAs) and oxidized lipid levels in vitro. Consistently, SeMet significantly decreased DOX-induced lipid peroxidation in H9C2 cells and mortality in C57BL/6 mice compared to DXZ, ferrostatin-1, and normal saline. SeMet can effectively reduce serum markers of cardiac injury in C57BL/6 mice and breast Cancer patients. Depletion of the GPX4 gene in C57BL/6 mice resulted in an increase in polyunsaturated fatty acid (PUFA) levels and eliminated the protective effect of SeMet against DIC. Notably, SeMet exerted antitumor effects on breast Cancer models with DOX while providing cardiac protection for the same animal without detectable toxicities. These findings suggest that pharmacological activation of GPX4 is a valuable and promising strategy for preventing the cardiotoxicity of doxorubicin.

Keywords

Cardiotoxicity; DOX; GPX4; Selenium; scRNA-seq.

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