Iron Overload and Excitotoxicity: Connecting Ferroptosis with Epileptic Seizures

Epilepsy diagnosis requires the occurrence of at least one seizure, while status epilepticus (SE) is a life-threatening condition with prolonged seizures without a return to baseline consciousness, often requiring emergency intervention. Epilepsy is a chronic neurological disorder with neurobiological, cognitive, psychological, and social complications. It is characterized by the recurrence of unprovoked seizures that last from seconds to hours per seizure. The precise pathophysiology of epilepsy remains unclear despite extensive research, and several predisposing factors contribute to its occurrence, such as head injury, stroke, genetic predispositions, or infection. Ferroptosis is an iron-mediated, regulated form of cell death driven by overload of iron, leading to accumulation of reactive oxygen species (ROS). It has been considered in recent research as a contributing mechanism to predisposing lipid peroxidation and causing implication in several neurological disorders, including epilepsy. According to recent studies, ferroptosis inhibition is probably a successful treatment strategy for epilepsy. This review article provides an insight into the ferroptosis axis and the related pathogenesis, highlighting the key regulatory elements such as peroxidase 4 (GPX4), system Xc⁻, and iron metabolism. It further explores how dysregulation of these elements may contribute to epileptogenesis and seizure propagation, with the aim of finding novel therapeutic targets in epilepsy to improve the management and treatment outcomes of patients suffering from this debilitating condition.