Redox Biology (Apr 2024)
Pharmacological activation of GPX4 ameliorates doxorubicin-induced cardiomyopathy
- Chuying Huang,
- Yishan Guo,
- Tuo Li,
- Guogen Sun,
- Jinru Yang,
- Yuqi Wang,
- Ying Xiang,
- Li Wang,
- Min Jin,
- Jiao Li,
- Yong Zhou,
- Bing Han,
- Rui Huang,
- Jiao Qiu,
- Yong Tan,
- Jiaxing Hu,
- Yumiao Wei,
- Bo Wu,
- Yong Mao,
- Lingshan Lei,
- Xiusheng Song,
- Shuijie Li,
- Yongsheng Wang,
- Tao Zhang
Affiliations
- Chuying Huang
- 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; Corresponding author. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Yishan Guo
- 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
- Tuo Li
- 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
- Guogen Sun
- 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
- Jinru Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Yuqi Wang
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Ying Xiang
- 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
- Li Wang
- 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
- Min Jin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Jiao Li
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Yong Zhou
- Hubei Selenium and Human Health Institute, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, 445000, China
- Bing Han
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, 150081, China
- Rui Huang
- 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
- Jiao Qiu
- 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
- Yong Tan
- 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
- Jiaxing Hu
- 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
- Yumiao Wei
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Bo Wu
- 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
- Yong Mao
- Wuhan Frasergen Bioinformatics Co. Ltd., Wuhan, 430070, China
- Lingshan Lei
- Wuhan Frasergen Bioinformatics Co. Ltd., Wuhan, 430070, China
- Xiusheng Song
- 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
- Shuijie Li
- State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Biopharmaceutical Sciences, College of Pharmacy, Harbin Medical University, Harbin, 150081, China; Corresponding author.
- Yongsheng Wang
- Division of Thoracic Tumor Multimodality Treatment, Cancer Center, Sichuan University, West China Hospital, Chengdu, 610041, China; Corresponding author.
- Tao Zhang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Corresponding author.
- Journal volume & issue
-
Vol. 70
p. 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.
