Exogenous Maresin1 attenuates doxorubicin-induced cardiomyocyte ferroptosis and mitochondrial impairment via NRF2/GPX4 axis

  • Free Radic Biol Med. 2025 Aug 1:235:335-346. doi: 10.1016/j.freeradbiomed.2025.05.388.
Fengyuan Wang  1 ,  Wei Zhang  2 ,  Lin Yin  3 ,  Congxin Huang  3 ,  Hongyi Zhao  4
Affiliations
  • 1. Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, 430060, PR China. Electronic address: [email protected].
  • 2. Department of Cardiology, The First College of Clinical Medical Science, China Three Gorges University, Yichang, 443000, PR China.
  • 3. Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, 430060, PR China.
  • 4. Department of Cardiology, Renmin Hospital of Wuhan University, Cardiovascular Research Institute, Wuhan University, Hubei Key Laboratory of Cardiology, Wuhan, 430060, PR China. Electronic address: [email protected].
PMID: 40348287 DOI: 10.1016/j.freeradbiomed.2025.05.388
Abstract

Doxorubicin (Dox)-induced cardiotoxicity in patients with Cancer, mediated primarily through cardiomyocyte Ferroptosis and mitochondrial dysfunction, presents both life-threatening risks and significant limitations to Dox chemotherapeutic efficacy. The study investigated the therapeutic potential and mechanistic role of Maresin1-a novel proinflammatory regression mediator (SPM) -in Dox-induced cardiomyocyte Ferroptosis. We employed both in vitro and in vivo models: H9C2 cells and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for in vitro Ferroptosis modeling and C57BL/6 mice for in vivo validation. Our key findings showed that Maresin1 in Dox-treated cardiomyocytes attenuated lipid peroxidation, upregulated the anti-ferroptosis-related protein expression via the NRF2/GPX4 axis and mitigated mitochondrial structural and functional impairment. However, inhibition of NRF2 signaling abolished the cardioprotective effects of Maresin1 against Dox-induced Ferroptosis. In conclusion, Maresin1 preserved cardiac function by preventing Dox-associated cardiomyocyte Ferroptosis and mitochondrial impairment through the NRF2/GPX4 axis activation.

Keywords
Cardiomyocyte ferroptosis; Doxorubicin; Maresin1; Mitochondrial impairment; NRF2 signaling.
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