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<p>Ischemic stroke (IS) remains a leading cause of death and disability worldwide; however, effective neuroprotective therapies are lacking. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key contributor to neuronal injury following cerebral ischemia. Epigenetic mechanisms, including DNA methylation, histone modification, and microRNA (miRNA) regulation, critically modulate ferroptosis-related gene expression. This review systematically examines how epigenetic modifications regulate ferroptosis in IS by influencing iron homeostasis, antioxidant defense systems, and lipid metabolism. We highlighted key regulatory axes, such as DNMT-mediated GPX4 and PINK1 methylation, HDAC-regulated iron uptake and antioxidant defense, ubiquitination-dependent SLC7A11 and ACSL4 regulation, and miRNA/ferroptosis-related targets. Furthermore, we discuss the therapeutic potential of targeting these epigenetic-ferroptosis interactions for IS treatment. Understanding these mechanistic links may facilitate the development of novel epigenetic-based strategies to inhibit ferroptosis and improve the outcomes of patients with IS.</p> Graphical Abstract <p>Epigenetic Regulation and Ferroptosis in IS: Disrupted iron metabolism in the brain under ischemic conditions, coupled with oxidative stress and imbalanced lipid peroxidation, collectively exacerbates ferroptosis. Epigenetic mechanisms are also involved in this process. Targeting of these epigenetic mechanisms offers a viable avenue for mitigating ferroptosis following IS. LOOH: lipid hydroperoxide; ROS: reactive oxygen species.</p>

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Epigenetic Mechanisms Regulating Ferroptosis in Ischemic Stroke: From Pathogenesis to Therapeutic Targets

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月25日

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  • Jiale Gan,
  • Xinyi Yang,
  • Jianan Wu,
  • Ziyan Cai,
  • Xianglong Zhai,
  • Yang Wu,
  • Wenlei Li,
  • Minghua Wu

摘要

Ischemic stroke (IS) remains a leading cause of death and disability worldwide; however, effective neuroprotective therapies are lacking. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a key contributor to neuronal injury following cerebral ischemia. Epigenetic mechanisms, including DNA methylation, histone modification, and microRNA (miRNA) regulation, critically modulate ferroptosis-related gene expression. This review systematically examines how epigenetic modifications regulate ferroptosis in IS by influencing iron homeostasis, antioxidant defense systems, and lipid metabolism. We highlighted key regulatory axes, such as DNMT-mediated GPX4 and PINK1 methylation, HDAC-regulated iron uptake and antioxidant defense, ubiquitination-dependent SLC7A11 and ACSL4 regulation, and miRNA/ferroptosis-related targets. Furthermore, we discuss the therapeutic potential of targeting these epigenetic-ferroptosis interactions for IS treatment. Understanding these mechanistic links may facilitate the development of novel epigenetic-based strategies to inhibit ferroptosis and improve the outcomes of patients with IS.

Graphical Abstract

Epigenetic Regulation and Ferroptosis in IS: Disrupted iron metabolism in the brain under ischemic conditions, coupled with oxidative stress and imbalanced lipid peroxidation, collectively exacerbates ferroptosis. Epigenetic mechanisms are also involved in this process. Targeting of these epigenetic mechanisms offers a viable avenue for mitigating ferroptosis following IS. LOOH: lipid hydroperoxide; ROS: reactive oxygen species.