Ferroptosis in drug-resistant epilepsy: Molecular mechanisms, evidence, and therapeutic targets

Drug-resistant epilepsy (DRE) affects approximately one-third of people with epilepsy and is associated with persistent seizures, progressive neuronal injury, cognitive comorbidity, and increased mortality. Current antiseizure medications primarily modulate neuronal excitability and do not directly address the cellular injury mechanisms that may sustain epileptogenesis and pharmacoresistance. Objective: This narrative review evaluates the evidence linking ferroptosis an iron-dependent, lipid-peroxidation-driven form of regulated cell death—to epilepsy and DRE, and identifies potential therapeutic targets. Evidence from experimental seizure models, human temporal lobe epilepsy tissue, and mechanistic studies was synthesized around iron dysregulation, the system xc−/glutathione peroxidase 4 (GPX4) axis, lipid peroxidation, oxidative stress, Nrf2/Keap1 signalling, and drug-transport mechanisms. Ferroptosis-related changes, including iron accumulation, GPX4 downregulation, glutathione depletion, and increased 4-hydroxynonenal and malondialdehyde, have been reported in kainate, pentylenetetrazole, pilocarpine, ferric-chloride, and human temporal lobe epilepsy settings. Ferroptosis inhibitors, iron chelation, Nrf2/Keap1 activation, and selected repurposed compounds reduce seizures or neuronal injury in experimental models. Ferroptotic injury may converge with transporter- and target-mediated mechanisms of pharmacoresistance, although the direction and clinical importance of this relationship remain uncertain. Ferroptosis is a plausible and experimentally tractable contributor to neuronal injury and pharmacoresistance in DRE. Biomarker validation, mechanistic bridging studies, and carefully designed early-phase trials particularly of repurposable agents such as deferoxamine are needed before ferroptosis-directed treatment can be translated to clinical epilepsy care.