Ironing out the Links: Ferroptosis in epilepsy and SUDEP

Iron is a crucial element for almost all organisms because it plays a vital role in oxygen transport, enzymatic processes, and energy generation due to its electron transfer capabilities. However, its dysregulation can lead to a form of programmed cell death known as ferroptosis, which is characterized by cellular iron accumulation, reactive oxygen species (ROS) production, and unrestricted lipid peroxidation. Both iron and ferroptosis have been identified as key players in the pathogenesis of various neurodegenerative diseases. While in epilepsy this phenomenon remains relatively understudied, seizures can be considered hypoxic-ischemic episodes resulting in increased ROS production, lipid peroxidation, membrane disorganization, and cell death. All of this is accompanied by elevated intracellular free Fe²⁺ concentration and hemosiderin precipitation, as existing reports suggest a significant accumulation of iron in the brain and heart associated with epilepsy. Generalized tonic-clonic seizures (GTCS), a primary risk factor for Sudden Unexpected Death in Epilepsy (SUDEP), not only have an impact on the brain but also lead to cardiogenic dysfunctions associated with "Iron Overload and Cardiomyopathy" (IOC) and "Epileptic heart" characterized by electrical and mechanical dysfunction and a high risk of malignant bradycardia. In line with this phenomenon, studies conducted by our research group have demonstrated that recurrent seizures induce hypoxia in cardiomyocytes, resulting in P-glycoprotein (P-gp) overexpression, prolonged Q-T interval, severe bradycardia, and hemosiderin precipitation, correlating with an elevated spontaneous death ratio. In this article, we explore the intricate connections among ferroptosis, epilepsy, and SUDEP. By synthesizing current knowledge and drawing insights from recent publications, this study provides a comprehensive understanding of the molecular underpinnings. Furthermore, this review offers insights into potential therapeutic avenues and outlines future research directions.