Epilepsy is a neurological disorder characterized by recurrent seizures, resulting from abnormal brain activity [1]. Various factors can contribute to the occurrence of epilepsy, including genetic predisposition, brain injuries, and metabolic disorders [2]. Current treatment options for epilepsy mainly rely on antiepileptic drugs (AEDs), but approximately one-third of patients are unresponsive to medication [3]. This highlights the need for personalized treatment strategies and the exploration of new therapeutic approaches. Understanding the specific molecular mechanisms underlying epilepsy is crucial for developing targeted therapies. It holds significant clinical significance in improving the management and outcomes for epilepsy patients.

Ferroptosis, as a newly defined iron-dependent regulated cell death, is characterized by the accumulation of lipid reactive oxygen species (ROS) and mitochondrial abnormalities [4]. It is closely associated with oxidative stress [5]. Until now, only a limited number of research articles regarding the relationship between epilepsy and ferroptosis were published and there is still a scarcity of literature addressing the molecular mechanisms involved. Previous studies have suggested that inhibiting ferroptosis could be an effective therapeutic approach for epilepsy, indicating that ferroptosis may represent a new strategy and direction for epilepsy treatment [6]. For instance, Ye et al. documented that ferrostain-1, an inhibitor of ferroptosis, suppressed cognitive impairment in epileptic rats by deactivating P38 mitogen-activated protein kinase [7]. Another study reported that the clinical-stage therapeutic vatiquinone (EPI-743) attenuated seizure by inhibiting ferroptosis in conditions characterized by GSH depletion and excessive iron levels [8]. This highlights the close connection between iron death, oxidative stress, and their significance in the progression of epilepsy.

CircRNA SLC8A1 (circSLC8A1) is a circular RNA derived from the SLC8A1 gene [9]. SLC8A1 encodes the sodium/calcium exchanger 1 (NCX1) protein, which is involved in calcium homeostasis and plays a crucial role in neuronal function [10]. Previous studies have reported the dysregulation of circSLC8A1 in various neurological disorders, particularly highlighting its involvement in oxidative stress and the progression of neurodegenerative diseases [9]. For example, in Parkinson's disease, circSLC8A1 has been found to be downregulated, and its decreased expression is associated with increased oxidative stress and neuronal cell death [9]. Additionally, in Alzheimer's disease, circSLC8A1 has been shown to modulate the expression of genes related to oxidative stress and neuroinflammation, suggesting its role in disease pathogenesis [11]. Nevertheless, the potential involvement of circSLC8A1 in epilepsy progression, particularly in relation to ferroptosis and oxidative stress remains unclear.

The glutamate/cystine exchanger (SLC7A11), also known as xCT, is responsible for facilitating the exchange of cystine and glutamate across the cell membrane [12]. SLC7A11 has been implicated in various physiological and pathological processes, including cancer, neurodegenerative diseases, and immune responses [[12], [13], [14]]. Studies have indicated that SLC7A11 may promote cancer progression by inhibiting cancer cell ferroptosis [15], suggesting its potential role in regulating cell ferroptosis. Furthermore, it has been reported that the expression level of SLC7A11 was elevated in glioma patients, and high SLC7A11 expression was closely correlated with epileptic seizures in glioma patients at diagnosis [16]. Another study further confirmed that SLC7A11 expression was positively associated with glutamate release from gliomas and peritumoral seizures [17].

Building upon these findings, the focus of this study is to investigate the potential involvement of circSLC8A1 and SLC7A11 in epilepsy progression, particularly in relation to iron death and oxidative stress. This study found that circSLC8A1 and Transcription Factor 3 (ATF3) had a negative correlation with SLC7A11. CircSLC8A1 triggered SLC7A11 neuronal ferroptosis by recruiting with Fused in Sarcoma (FUS) to stabilize activating ATF3 mRNA expression. The induced neuronal ferroptosis facilitates epilepsy progression. This study may advance our understanding of epilepsy disease and pave the way for potential therapeutic strategies.