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

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

• Level A · Stronger Clinical Evidence
• Level B · Emerging clinical evidence with positive signals
• Level C · Early human research exploring benefits
• Level D · Scientific groundwork from lab and animal studies
• Emerging · Emerging topic under active research

Abstract (original English)

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.

Evidence level

Evidence from laboratory and animal studies provides groundwork for understanding mechanisms and potential before human studies continue.

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