The role of ferroptosis in epilepsy: mechanisms and targeted therapies.

Abstract

Epilepsy is a common chronic neurological disorder. Approximately one-third of patients respond poorly to existing anti-seizure medications. There is an urgent need for novel therapeutic strategies targeting the fundamental disease processes. Ferroptosis is an iron-dependent form of regulated cell death characterized by the accumulation of lipid peroxides. In recent years, its role in the pathological mechanisms of epilepsy has gained increasing attention. This review systematically elaborates the core molecular mechanisms of ferroptosis. These include dysregulated iron metabolism, failure of the glutathione peroxidase 4 (GPX4) antioxidant defense system, and excessive activation of lipid peroxidation. The article focuses on summarizing experimental and clinical evidence linking ferroptosis to the onset and progression of epilepsy. It reveals key alterations in ferroptosis markers in the brain tissues of epilepsy patients and model animals. Furthermore, it delves into the complex molecular regulatory networks involved. These networks encompass neuron-glia interactions (e.g., the C-X-C Motif Chemokine Ligand 10 (CXCL10)/C-X-C Motif Chemokine Receptor 3 (CXCR3) axis), MicroRNAs/non-coding RNAs, the nuclear factor erythroid 2-related factor 2 (Nrf2), mitochondrial dysfunction, and neuroinflammation. Based on this evidence, the article further evaluates the therapeutic potential of targeting ferroptosis. This covers emerging strategies such as direct inhibitors (e.g., Ferrostatin-1), natural compounds (e.g., quercetin, boswellic acid), drug repurposing (e.g., troglitazone, D-penicillamine), gene therapy and targeted delivery systems, as well as bioinformatics-guided target discovery. Finally, this review outlines future research directions and challenges. These include elucidating cell-specific mechanisms, developing non-invasive biomarkers, optimizing combination therapies, and promoting clinical translation. The aim is to provide new perspectives and a theoretical foundation for developing disease-modifying therapies for epilepsy.

Key Findings

• Ferroptosis, an iron-dependent regulated cell death, plays a significant role in the pathogenesis of epilepsy.
• Key molecular mechanisms include dysregulated iron metabolism, failure of the GPX4 antioxidant defense system, and excessive lipid peroxidation.
• The NRF2 pathway is involved in the complex regulatory networks influencing ferroptosis in epilepsy, alongside neuron-glia interactions, microRNAs/non-coding RNAs, mitochondrial dysfunction, and neuroinflammation.
• Therapeutic strategies targeting ferroptosis, such as direct inhibitors (Ferrostatin-1), natural compounds (quercetin, boswellic acid), drug repurposing, gene therapy, and targeted delivery systems, show promise for epilepsy treatment.

Clinical Significance

Citation

Shen Dingding, Zhao Zihao, Ji Yananet al.. The role of ferroptosis in epilepsy: mechanisms and targeted therapies. Biochemical pharmacology. 2026-Mar-20.