Mechanism of Keap1-Nrf2-HO-1/GPX4 signal in blocking epileptic hippocampal neuron ferroptosis and intervention effect of Caogouzhimu decoction

Background: The pathogenesis of epilepsy is closely associated with ferroptosis in hippocampal neurons. The Keap1-Nrf2-HO-1/GPX4 signaling pathway serves as a crucial endogenous antioxidant system and plays a significant role in regulating cellular ferroptosis. Caogouzhimu decoction has demonstrated potential antiepileptic effects in clinical practice, yet whether it intervenes in neuronal ferroptosis via this signaling pathway remains unclear. Objective: To explore the mechanism of the Keap1-Nrf2-HO-1/GPX4 signaling pathway in ferroptosis of hippocampal neurons in epilepsy and evaluate the intervention effect of Caogouzhimudecoction. Methods: Fifty mice were divided into a blank control group, a model control group and low-, medium- and high-dose Caogouzhimu decoction groups, with ten mice per group. The epilepsy model was induced by PTZ and the treatment groups received intragastric administration of Caogouzhimu decoction at doses of 40, 80 and 120 mg/mL, respectively. Behavior, hippocampal dentate gyrus neurogenesis and the expression levels of components related to the Keap1-Nrf2-HO-1/GPX4 signaling pathway were compared among the groups. Results: The high-dose group exhibited significantly shorter latency, reduced swimming distance and fewer convulsions above grade II compared to the other groups (P<0.05). Furthermore, the high-dose treatment effectively suppressed neurogenesis in the hippocampal dentate gyrus and the occurrence of ferroptosis, as evidenced by significantly lower mRNA expression levels of Keap1, Nrf2, HO-1 and GPX4 compared to those in the low- and medium-dose groups (P<0.05). Conclusion: Caogouzhimu decoction exerts anti-epileptic effects, likely by inhibiting hippocampal neuronal ferroptosis through modulation of the Keap1-Nrf2-HO-1/GPX4 signaling pathway. These findings provide a novel perspective for the clinical treatment of epilepsy.