Epilepsy, a prevalent brain disorder in the field of neurology (Fisher et al., 2005), remains undertreated, with approximately 75% of individuals worldwide not receiving effective treatment, especially in low- and middle-income countries, leading to a significant global treatment gap (Saxena and Li, 2017). Furthermore, epilepsy can be life-threatening, with a mortality rate five times greater than that of the general population, as it can result in sudden death during seizures (Thurman et al., 2014). Current studies are focused on exploring the pathogenesis of epilepsy. While drug treatment aims to alleviate clinical symptoms, approximately one-third of epilepsy patients develop drug resistance, leading to refractory epilepsy (Catala et al., 2020). Antiepileptic drugs often have severe side effects and poor patient compliance and may progress to persistent status epilepticus (Işık et al., 2015). Animal models of temporal lobe epilepsy (TLE), a common form of drug-resistant epilepsy, are frequently used as representative models for studying epilepsy. In patients with drug-resistant epilepsy, surgical removal of the epileptic lesion is an effective treatment option (Cui et al., 2019). However, surgical treatment, while effective, is invasive and expensive and carries potential health risks after the procedure. Therefore, it is crucial to prioritize the development and investigation of new potential antiepileptic drugs.

Iron is an important element in the human body that plays a vital role in various physiological processes, including cell proliferation and the immune response (Johnson and Wessling-Resnick, 2012). To prevent the harmful effects of free iron, transferrin is converted into ferritin, which is primarily stored in the liver and regulates iron balance in the body (Xu et al., 2010). The absorption of iron in the body mostly occurs in the duodenal region, emphasizing the significance of regulating intestinal iron absorption in maintaining iron homeostasis (Mastrogiannaki et al., 2013). Additionally, disturbances in iron homeostasis in the brain have been linked to various brain diseases, such as Alzheimer's disease and Parkinson's disease (Ward et al., 2014). Studies utilizing magnetic resonance imaging (MRI) techniques have revealed cortical iron deposits in patients with epilepsy. Additionally, animal models have shown increased ferritin levels and seizures induced by cortical iron injections, indicating a potential association between iron overload and epilepsy development (Khoury et al., 2019). However, limited studies have been conducted on the role of iron homeostasis in temporal lobe epilepsy.

Given the potential relevance of iron homeostasis to epilepsy, targeted removal of excess iron may play a role in the development of epilepsy. The use of iron chelators to remove excess iron has proven to be an effective approach when iron homeostasis is dysregulated and excess iron accumulates in the body (Kotila, 2012). Deferasirox (DFX), a novel oral iron chelator, is a nonchiral tridentate ligand of trivalent iron that selectively binds iron without causing iron excretion. It is cost-effective, has a long half-life, and has few adverse effects; therefore, it is increasingly preferred as a treatment for transfusion iron overload in thalassemia patients. (Díaz-García et al., 2014; Sadaf et al., 2018; Tanaka, 2014).

Inositol 1,4,5-triphosphate receptor interacting protein (ITPRIP), also known as DANGER, is a protein containing the MAB-21 structural domain. It binds to the inositol 1,4,5-trisphosphate receptor (IP3R), a key regulator of intracellular Ca2+ signaling (Kang et al., 2010). Inositol 1,4,5-trisphosphate (IP3) is involved in activating G protein-coupled receptors or receptor tyrosine kinase receptors located at the plasma membrane, which leads to IP3R-mediated Ca2+ release from endoplasmic reticulum stores. ITPRIP physiologically binds to IP3R and enhances its potency in an allosteric manner, inhibiting IP3R-mediated Ca2+ release without affecting ligand binding (van Rossum et al., 2006). The activity of ITPRIP is tightly regulated by molecules that interact with IP3R-binding proteins released from inositol 1,4,5-trisphosphate, Huntington's protein, progerin, DANGER, and cytochrome c. Disruptions in this regulation result in elevated intracellular calcium ions, contributing to various diseases (Kawaai et al., 2009). Some studies have demonstrated that ITPRIP interacts with the postsynaptic transmembrane protein neuroligin 3 (NLGN3), which plays a crucial role in neuronal synapse formation and glial neuron communication (Shen et al., 2015a). Studies have confirmed that mice lacking the Itprip gene exhibit more severe brain damage after acute excitotoxicity and transient cerebral ischaemia than control mice. This finding suggested that ITPRIP may physiologically regulate neuronal viability and could be a potential therapeutic target for stroke and neurodegenerative diseases.

ITPRIP is closely associated with the nervous system and neuronal development. The relationship between ITPRIP and epilepsy is an area of research that requires further investigation. In this study, we investigated the effects of the iron chelator DFX and iron supplementation on epileptic mice. Our findings demonstrate, for the first time, that interventions in iron homeostasis can affect seizures. Using whole-cell membrane clamp techniques, we discovered that DFX exerts its antiepileptic effects by influencing excitatory synaptic transmission. Importantly, we also observed that alterations in the ITPRIP gene can have an antiepileptic effect by regulating iron homeostasis. This study aimed to elucidate the mechanism by which DFX relieves epilepsy, revealing a potential new target for epilepsy control and treatment. Herein, we provide a clear explanation of how DFX works and its implications for the diagnosis and treatment of epilepsy.