2. Academic Validation
  3. Targeting GPX4 alleviates ferroptosis and retards abdominal aortic aneurysm formation

Targeting GPX4 alleviates ferroptosis and retards abdominal aortic aneurysm formation

  • Biochem Pharmacol. 2025 Apr:234:116800. doi: 10.1016/j.bcp.2025.116800.
Yu Shi 1,  Yi Zhao 1,  Si-Jia Sun 1,  Xiu-Ting Lan 1,  Wen-Bin Wu 2,  Zhen Zhang 1,  Yu-Xin Chen 1,  Yu-Ying Yan 3,  Yu-Ping Xu 1,  Dong-Jie Li 4,  Hui Fu 5,  Fu-Ming Shen 6
Affiliations

Affiliations

  • 1 Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
  • 2 Department of Pharmacology, School of Pharmacy, Second Military Medical University/Naval Medical University, Shanghai, China.
  • 3 School of Pharmacy, Nanjing Medical University, Nanjing, China.
  • 4 Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: djli@tongji.edu.cn.
  • 5 Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: 1610617@tongji.edu.cn.
  • 6 Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: fumingshen@tongji.edu.cn.
PMID: 39952331 DOI: 10.1016/j.bcp.2025.116800
Abstract

Abdominal aortic aneurysm (AAA) is a potentially fatal Cardiovascular Disease, closely related to inflammation and loss of vascular smooth muscle cells (VSMCs). Ferroptosis is an iron-dependent cell death associated with peroxidation of lipids. However, the direct role of Glutathione Peroxidase 4 (GPX4) itself determined Ferroptosis in the course of AAA pathogenesis remains unknown. Here, we reported that Ferroptosis was triggered in human AAA, elastase- and angiotensin II (Ang II)-induced mouse AAA, and Ang II-incubated VSMCs. Inhibition of Ferroptosis via global genetic overexpression of GPX4, a critical anti-ferroptosis molecule, markedly prevented both vascular remodeling and inflammatory response. Mechanistically, GPX4 changed the migration and activation of macrophages/monocytes in AAA tissues in mice. Experiments in vitro demonstrated that overexpression of GPX4 prevented the JAK1/STAT3 signaling activation in VSMCs induced by IL-6, production of pro-inflammatory macrophages. Finally, the role of Ferroptosis was confirmed on an Ang II-induced mice AAA model. These results emphasized the significance of Ferroptosis in AAA, and provided novel insights that therapy focusing on GPX4 might be a promising strategy for treatment of AAA in the clinic.

Keywords

Abdominal aortic aneurysm; Ferroptosis; GPX4; Immune cells; Vascular smooth muscle cells.

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