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<p>Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation. It plays a crucial role in various pathological conditions, including neurodegenerative diseases, cancer, ischemia–reperfusion injury, and organ failure. This review systematically explores the key mechanisms underlying ferroptosis, including polyunsaturated fatty acid-containing phospholipid (PUFA-PL) peroxidation, iron metabolism, and mitochondrial dysfunction. Additionally, we summarize major endogenous ferroptosis defense systems, including the SLC7A11-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, the ferroptosis suppressor protein 1 (FSP1)-ubiquinol (CoQH₂) system, the mitochondrial dihydroorotate dehydrogenase (DHODH)-CoQH₂ pathway, and the guanosine triphosphate cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway, which act as critical brakes on ferroptosis. Furthermore, we discuss various small-molecule inhibitors targeting ferroptosis, categorized by their mechanisms of action, including iron chelators, lipid peroxidation inhibitors, antioxidants, and regulatory pathway modulators. Recent advances in pharmacological strategies and their potential therapeutic applications are also highlighted.</p>

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Ferroptosis inhibitors: mechanisms of action and therapeutic potential

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年12月19日

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  • Kun Duo,
  • Xiaona Feng,
  • Xiaofang Tian,
  • Fang Wang,
  • Yaxing Zhao,
  • Jianqiang Yu,
  • Yue Liu,
  • Yuan He,
  • Zhenyu Cai

摘要

Ferroptosis is a regulated form of cell death characterized by iron-dependent lipid peroxidation. It plays a crucial role in various pathological conditions, including neurodegenerative diseases, cancer, ischemia–reperfusion injury, and organ failure. This review systematically explores the key mechanisms underlying ferroptosis, including polyunsaturated fatty acid-containing phospholipid (PUFA-PL) peroxidation, iron metabolism, and mitochondrial dysfunction. Additionally, we summarize major endogenous ferroptosis defense systems, including the SLC7A11-glutathione (GSH)-glutathione peroxidase 4 (GPX4) axis, the ferroptosis suppressor protein 1 (FSP1)-ubiquinol (CoQH₂) system, the mitochondrial dihydroorotate dehydrogenase (DHODH)-CoQH₂ pathway, and the guanosine triphosphate cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4) pathway, which act as critical brakes on ferroptosis. Furthermore, we discuss various small-molecule inhibitors targeting ferroptosis, categorized by their mechanisms of action, including iron chelators, lipid peroxidation inhibitors, antioxidants, and regulatory pathway modulators. Recent advances in pharmacological strategies and their potential therapeutic applications are also highlighted.