Ferroptosis, an iron-dependent form of regulated cell death characterized by lipid peroxidation, has emerged as a potential contributor to neuronal injury across neurological disorders. Increasing evidence suggests that ferroptotic mechanisms may participate in the pathophysiology of epilepsy, linking sustained oxidative stress, iron dysregulation, and progressive neuronal loss. Mechanistically, ferroptosis is driven by disruption of the canonical system Xc − –glutathione–glutathione peroxidase 4 axis, resulting in impaired detoxification of lipid hydroperoxides and membrane damage accumulation. Neurons are particularly susceptible due to high oxygen consumption, abundant polyunsaturated fatty acids, and vulnerability to iron-catalyzed reactive oxygen species generation. Experimental studies and gene expression analyses have identified ferroptosis-related pathways enriched in epileptic tissue, while human biomarker investigations demonstrate reduced glutathione levels and elevated lipid peroxidation products in patients with epilepsy. Although most therapeutic data derive from preclinical rodent models, pharmacological modulation of ferroptosis – via iron chelation or inhibition of lipid peroxidation – has shown seizure-reducing and neuroprotective effects. Importantly, ferroptosis likely operates alongside other regulated cell death pathways rather than acting as a singular mechanism. Shared features of iron accumulation and lipid peroxidation in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, further support a broader pathogenic relevance. Continued translational investigation is necessary to determine whether targeting ferroptosis may offer disease-modifying strategies in epilepsy.
Khan et al. (Tue,) studied this question.