1. Academic Validation
  2. ALOX15 Modulates Ferroptosis via the Reactive Oxygen Species-Mediated MAPK Pathway in Doxorubicin-Induced Cardiotoxicity

ALOX15 Modulates Ferroptosis via the Reactive Oxygen Species-Mediated MAPK Pathway in Doxorubicin-Induced Cardiotoxicity

  • Antioxid Redox Signal. 2025 Jun 2. doi: 10.1089/ars.2023.0468.
Xingang Sun 1 Lu Chen 2 Jie Han 2 Weixun Cai 3 Shan Li 2 Ting Chen 2 Miao Chen 4 Han Zhang 2 Yuxian He 1 Liangrong Zheng 2 Lihong Wang 1
Affiliations

Affiliations

  • 1 Department of Cardiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
  • 2 Department of Cardiology and Atrial Fibrillation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
  • 3 Heart Center, Department of Electrocardiographic and Cardiac Examination, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
  • 4 Department of Cardiovascular Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.
Abstract

Aims: Doxorubicin (Dox) is a potent chemotherapy agent, yet its clinical use is hampered by cardiotoxicity. Although extensive research has focused on Dox-induced cardiotoxicity (DIC), its mechanism remains elusive. Recent evidence implicates Ferroptosis as a key contributor to DIC. The 15-lipoxygenase-1 (ALOX15), involved in lipid peroxidation, is known to play an essential role in ischemia-induced myocardial damage and heart failure; however, its function in DIC is undefined. This study seeks to elucidate the role of ALOX15 in DIC and unravel its underlying mechanism. Results: Both ALOX15 mRNA and protein levels were elevated in DIC models in vivo and in vitro. Inhibition or silencing of ALOX15 ameliorated lipid peroxidation, Ferroptosis, and cardiac dysfunction in Dox-treated mice. Consistently, ALOX15 loss of function protected H9C2 cells against Dox and RSL3-induced toxicity. In addition, we found that linoleic acid increased the susceptibility of H9C2 cells toward Dox-induced damage, which was abolished by ALOX15 inhibition. Furthermore, Alox15 overexpression aggravated Dox-induced cell damage by aggravating Reactive Oxygen Species (ROS)-mediated Ferroptosis. Mechanistically, we discovered that the amelioration of Dox-induced Ferroptosis by ALOX15 loss of function occurred through inhibiting the ROS-mediated mitogen-activated protein kinase (MAPK) signaling pathway activation. Innovation and Conclusion: These results reveal that ALOX15 regulates Ferroptosis through ROS-mediated MAPK signaling pathway in DIC, suggesting a potential therapeutic target for DIC intervention. Antioxid. Redox Signal. 00, 000-000.

Keywords

ALOX15; cardiotoxicity; doxorubicin; ferroptosis; lipid peroxidation.

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