Ferroptosis and epilepsy: bidirectional pathogenic links and therapeutic implications

Abstract

Ferroptosis is a distinctive form of regulated cell death that is closely associated with various neurodegenerative disorders. In recent years, an increasing number of studies have demonstrated the crucial role of ferroptosis in the development and progression of epilepsy. Firstly, this article will review the existing research on the specific biological mechanism of ferroptosis in nerve injury, particularly in epilepsy, encompassing iron metabolism disorders and alterations in the expression of ferroptosis-related proteins. Secondly, with regards to treatment, this article will explore the application of ferroptosis inhibitors in antiepileptic therapy and their potential therapeutic effects. Additionally, it will focus on investigating the interaction between ferroptosis and existing antiepileptic drugs as well as the potential impact of strategies regulating ferroptosis on epilepsy treatment. Finally, we will evaluate both the progress made and limitations encountered in current research while proposing possible future directions for further exploration at the intersection of ferroptosis and epilepsy fields. These studies not only contribute to a better understanding of epileptic pathological mechanisms but also hold promise for providing novel insights and strategies for treating epilepsy.

Keywords: epilepsy; ferroptosis; iron metabolism; lipid peroxidation; reactive oxygen species.

Figure 1

Iron metabolism: The efficient delivery of Fe³⁺ to various organs is facilitated by the binding of plasma transporter TF. Upon binding to TFR1, TF facilitates the smooth transfer of iron ions into the cell interior and subsequent release of Fe³⁺. Subsequently, STEAP3 reduces Fe³⁺ and converts it to accessible Fe²⁺ within the cytoplasm. Through the DMT1 channel, Fe²⁺ can enter the cytoplasm and form a stable iron pool (LIP). Excess unbound Fe³⁺ can be exported outside the cell via FPN and subsequently oxidized back to Fe³⁺. As a crucial substrate for generating hydroxyl radical (OH) and hydroxide ion (OH-) through Fenton reaction, Fe²⁺ plays a pivotal role.

Figure 2

The System Xc- and GPX4 pathway: The conversion of cytoplasmic cysteine to glutathione (GSH) for tripeptide synthesis primarily occurs through the process ocess of glutamate-cysteine exchange, which involves a two-step enzymatic reaction: (1) Glutamic acid cysteine transaminase (GCL), also known as y-glutamyl cysteine synthetase (y-GCS); (2) Glutathione synthetase (GS). The major regulators of iron ptosis include GPX4, GSH, and System Xc-.

Figure 3

The lipid peroxidation: PUFAs are esterified to membrane phospholipids and subsequently react with ROS, thereby promoting cell ferroptosis. GPX4 uses GSH as a cofactor to enzymically reduce the lipid peroxides of polyunsaturated fatty acids to non-toxic lipid alcohols. Loss or inactivation of GPX4 results in the accumulation of lipid peroxides above normal levels, and in the presence of Fe²⁺ these lipid peroxides generate highly oxidized alkoxy groups. These alkoxy groups have the ability to directly damage adjacent PUFAs through free radical-mediated chain reactions, resulting in severe membrane damage.

Figure 4

Bidirectional pathogenic loop between ferroptosis and epilepsy. This schematic illustrates the self-reinforcing cycle linking ferroptosis and epilepsy through two interconnected axes: I. Epilepsy. Ferroptosis Pathway (Red Arrows) Seizure activity triggers glutamate excitotoxicity, inhibiting the cystine/glutamate antiporter (System Xc-). This depletes glutathione (GSH), inactivating GPX4 and enabling iron-dependent lipid peroxidation. Subsequent membrane rupture and neuronal death further potentiate epileptogenesis. II. Ferroptosis Epilepsy Pathway (Blue Arrows) Iron overload (e.g., post-hemorrhagic or metabolic) generates hydroxyl radicals (OH) via Fenton reactions. Reactive oxygen species (ROS) hyperexcite neurons through Nav channel dysregulation and mitochondrial dysfunction, establishing hyper-synchronous networks that lower seizure thresholds. Therapeutic Intervention Points (Yellow Stars): (1) Iron chelators (e.g., DFO): Block Fe²⁻-mediated ROS production. (2) GPX4 activators (e.g., Selenium): Restore lipid peroxide detoxification. (3) Radical-trapping antioxidants (e.g. Fer-1): Terminate lipid peroxidation chain reactions. The vicious cycle highlights ferroptosis as both cause and consequence of epilepsy, providing mechanistic targets for clinical intervention.

Figure 5

Iron-mediated ferroptosis core pathways in epilepsy (hippocampal neurons) and AMD (retinal pigment epithelium). Therapeutic targets (red stars): ① Iron chelation, ② GPX4 activation, ③ Antioxidant delivery.