Ferroptosis and Its Role in Epilepsy

Abstract

Epilepsy is one of the most common symptoms of many neurological disorders. The typical excessive, synchronous and aberrant firing of neurons originating from different cerebral areas cause spontaneous recurrent epileptic seizures. Prolonged epilepsy can lead to neuronal damage and cell death. The mechanisms underlying epileptic pathogenesis and neuronal death remain unclear. Ferroptosis is a newly defined form of regulated cell death that is characterized by the overload of intracellular iron ions, leading to the accumulation of lethal lipid-based reactive oxygen species (ROS). To date, studies have mainly focused on its role in tumors and various neurological disorders, including epilepsy. Current research shows that inhibition of ferroptosis is likely to be an effective therapeutic approach for epilepsy. In this review, we outline the pathogenesis of ferroptosis, regulatory mechanisms of ferroptosis, related regulatory molecules, and their effects on epilepsy, providing a new direction for discovering new therapeutic targets in epilepsy.

Keywords: GPx; GSH; epilepsy; ferroptosis; iron; lipid peroxidation.

FIGURE 1

Activation and inhibition mechanisms of ferroptosis. The Fe-mediated Fenton reaction, peroxidation of PUFA, and the redox of GSH/GPX4/system Xc- are the main biochemical events involved in ferroptosis. Excessive Fe²⁺ can donate electrons to generate hydroxyl radicals, which have high reactivity with biological molecules, leading to lipid peroxidation and the eventual development of ferroptosis. Activators and inhibitors in each stage of cellular iron metabolism, including iron uptake (e.g., IREs, HSPB1, and sulfasalazine), export (e.g., IREs), storage (e.g., FTMT and NCOA4), and turnover (e.g., iron chelating agents and FINO2), have close relations with ferroptosis. PUFAs are esterified into membrane phospholipids which then react with ROS and finally facilitate ferroptosis in the cells. Iron can increase the activity of ALOXs. Vitamin E could compete with ALOX at the substrate binding site against ferroptosis. PEBP1 increases the catalytic activity of ALOX15 by combining itself with ALOX15. GPX4, GSH, and system X_c^– are the main regulators of ferroptosis. System Xc- can be regulated at transcriptional and post-transcriptional stages by various ferroptosis inducers. p53 inhibits SLC7A11 expression. Erastin, sorafenib, and sulfasalazine can bind and inactivate SLC7A11. β-mercaptoethanol inhibits erastin-induced ferroptosis by increasing the intracellular concentration of cystine. BSO is an inhibitor of GSH biosynthesis, FIN56 promotes the degradation of GPX4, and RSL3 binds to GPX4 to directly inactivate GPX4. In addition, the FSP1-CoQ10-NADPH pathway is a stand-alone parallel anti-ferroptotic pathway. The NRF2-Keap1 protein complex also plays an important role in mediating lipid peroxidation and ferroptosis.

FIGURE 2

Iron metabolism in the human body. Fe³⁺ can be delivered into the cells by the binding of Tf and TFR1 in the cell membrane which is then transported to the endosome. Fe³⁺ is converted to Fe²⁺ in the endosome and is then released to a labile iron pool. Iron can be stored in ferritin in the cytoplasm and can also be exported by FPN. Ferritinophagy can modulate sensitivity to ferroptosis by the degradation of ferritin. Excess Fe²⁺ can donate electrons to lipid peroxidation via the Fenton reaction.