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A Doxorubicin-Induced Murine Model of Dilated Cardiomyopathy In Vivo
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Pharmacological activation of GPX4 ameliorates doxorubicin-induced cardiomyopathy

Chuying Huang1, Yishan Guo2, Tuo Li3

  • 1Cancer 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.

Redox Biology
|January 17, 2024
PubMed

Insights

Selenium supplementation with selenomethionine (SeMet) shows promise in preventing doxorubicin-induced cardiotoxicity by activating glutathione peroxidase 4 (GPX4). This approach reduces lipid peroxidation and cardiac damage without significant toxicities, offering a potential new strategy for cancer patients.

Area of Science:

  • Biochemistry
  • Cardiology
  • Oncology

Background:

  • Doxorubicin (DOX) chemotherapy is limited by cardiotoxicity, primarily linked to lipid peroxidation and iron overload.
  • Dexrazoxane (DXZ) is the sole FDA-approved drug for DOX-induced cardiomyopathy (DIC), but it has side effects and lacks preventive capabilities.

Purpose of the Study:

  • To investigate the potential of pharmacological activation of glutathione peroxidase 4 (GPX4) as a strategy to prevent DOX-induced cardiotoxicity.
  • To evaluate the efficacy and safety of selenomethionine (SeMet) in mitigating DOX-induced cardiac damage.

Main Methods:

  • Single-nucleus RNA sequencing (snRNA-seq) identified susceptible myocardial and epithelial cells.
  • In vitro and in vivo studies using H9C2 cells and C57BL/6 mice were conducted.
  • GPX4 gene depletion and comparisons with DXZ and ferrostatin-1 were performed.

Main Results:

  • SeMet significantly reduced polyunsaturated fatty acids (PUFAs) and oxidized lipids in vitro.
  • SeMet decreased DOX-induced lipid peroxidation and mortality in mice more effectively than DXZ.
  • SeMet reduced cardiac injury markers in mice and breast cancer patients, and demonstrated antitumor effects without toxicity.

Conclusions:

  • Pharmacological activation of GPX4 using SeMet is a promising strategy for preventing DOX-induced cardiotoxicity.
  • SeMet offers a safe and effective alternative for cardiac protection during DOX treatment.
  • Targeting lipid peroxidation via GPX4 activation presents a novel therapeutic avenue for managing chemotherapy side effects.
Keywords:
CardiotoxicityDOXGPX4SeleniumscRNA-seq

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