Circular RNA SLC8A1 triggers hippocampal neuronal ferroptosis by regulating FUS-mediated ATF3 mRNA stability in epilepsy

Background: Epilepsy is a neurological disorder characterized by recurrent seizures and is often unresponsive to current treatment options. Ferroptosis, a recently defined iron-dependent regulated cell death, has been suggested as a potential therapeutic target for epilepsy due to its association with oxidative stress. Additionally, circRNA SLC8A1 (circSLC8A1) has been implicated in various neurological disorders and oxidative stress-related diseases but its involvement in epilepsy progression, particularly in relation to ferroptosis and oxidative stress, remains unclear.Methods: qRT-PCR, Western blot, IHC and ELISA assays were employed to validate the relative expression of targeted genes and proteins. The levels of ROS, iron, LOP and GSH were detected by commercial kits. RNA pulldown and RIP assays were employed to detect the interactions among circSLC8A1, FUS and ATF3. A rat epilepsy model was established for further in vivo confirmation. Results and conclusion: In this study, we investigated the potential involvement of circSLC8A1 in epilepsy progression and its connection to ferroptosis and oxidative stress. Our findings demonstrate that circSLC8A1 triggers neuronal ferroptosis by stabilizing ATF3 mRNA expression through recruitment with FUS. The induced neuronal ferroptosis contributes to epilepsy progression. These results enhance our understanding of epilepsy pathogenesis and may provide insights for the development of novel therapeutic strategies.