Yang_2025_Discov.Med_37_871

BACKGROUND: Soman is a highly toxic organophosphorus nerve agent that can cause persistent neurotoxicity. However, the mechanism of soman-induced neurotoxicity has not been completely clarified. Ferroptosis, a novel type of programmed cell death, has been confirmed to precipitate neurotoxicity caused by organophosphorus flame retardant. Since studies on the relationship between ferroptosis and soman-induced neurotoxicity are lacking, the purpose of this research is to explore the mechanism of soman-induced neurotoxicity from the perspective of ferroptosis. METHODS: Institute of Cancer Research (ICR) mice were injected subcutaneously with low-dose soman (1/2 x median lethal dose (LD(50))) daily for seven consecutive days to evaluate the neurotoxic injury caused by soman through alterations in body weight, cholinesterase activity, and neuronal counting. The morphologic changes of neurons and levels of ferroptosis-related molecules, including glutamate, glutathione (GSH), system xc(-) (xCT), glutathione peroxidase 4 (GPX4), and malondialdehyde (MDA), were evaluated to confirm the involvement of ferroptosis in soman-induced neurotoxicity. The ferroptosis inhibitor ferrostatin-1 (Fer-1, 5 mg/kg) was administered daily immediately following soman exposure to further explore the role of ferroptosis. RESULTS: Repeated exposure to low-dose soman caused weight loss and neuronal death, and reduced cholinesterase activity. Meanwhile, it induced morphological changes of neurons characteristic of ferroptosis, increased glutamate and MDA levels, decreased GSH, and downregulated xCT and GPX4. Conversely, Fer-1 treatment mitigated neurotoxic injury and reversed the changes in ferroptosis-related molecule levels. CONCLUSION: These findings indicate that ferroptosis engages in the course of neurotoxicity caused by soman and exerts a harmful effect via the glutamate/xCT/GPX4 pathway. This study provides new potential therapeutic targets for countermeasures against soman exposure.