Zong_2025_Toxics_13_

Soman, an organophosphorus nerve agent, induces neurotoxicity primarily by inhibiting acetylcholinesterase, triggering a series of pathological events including cholinergic crisis, seizures, calcium overload, oxidative stress, mitochondrial dysfunction, and neuronal death. Nevertheless, the mechanisms underlying metabolic dysregulation-especially after repeated exposure-remain poorly characterized. To address this, we used SWATH-based proteomics to analyze changes in the hippocampal proteome following a repeated soman exposure regimen in a model of hippocampal injury. We identified 38 differentially expressed proteins, predominantly enriched in metabolic pathways. KEGG annotation indicated that these were mainly involved in carbohydrate, amino acid, and lipid metabolism, with specific roles in calcium signaling, tryptophan and tyrosine metabolism, alanine, aspartate and glutamate metabolism, and glyoxylate and dicarboxylate metabolism. Overall, our results demonstrate significant disruption of key metabolic pathways, particularly affecting carbohydrate and amino acid metabolism. We suggest that soman-induced hippocampal damage arises not only from acute calcium overload but also from persistent metabolic dysregulation that impairs energy production and biosynthetic processes. All of our preliminary results shed light on the nature of the biological process and target in the metabolism and provide basic research for the treatment, diagnosis, and prevention of nerve-agent-induced brain damage.