Sodium valproate induces pancreatic injury by disruption of one carbon metabolism

Objective: Valproate medications are a leading cause of drug-associated acute pancreatitis (DAAP), yet the underlying mechanisms remain unclear. This study aimed to determine how sodium valproate (Na-VPA) induces pancreatic injury and contributes to acute pancreatitis (AP). Methods: Freshly isolated murine pancreatic acinar cells (PACs) were treated with Na-VPA or major VPA metabolites, and cytotoxicity was assessed by spectrofluorometry and confocal imaging. In vivo , C57BL/6 mice were administered Na-VPA with or without caerulein-induced pancreatitis (CER-AP), and pancreatic injury was evaluated by biochemical and histological analyses. Pancreatic mRNA-sequencing and pseudo-targeted metabolomics were conducted to identify dysregulated pathways. Intracellular methionine-cycle metabolites were quantified by LC-MS/MS, while expression of one-carbon metabolism enzymes was determined by RT-qPCR and western blotting. AutoDock Vina was employed to predict binding affinities of VPA to key metabolic enzymes. The therapeutic effect of S-adenosylmethionine (SAM) supplementation on Na-VPA-exacerbated CER-AP was also tested. Results: Na-VPA and its metabolites induced concentration- and time-dependent PAC death, independent of toxic calcium signaling. In vivo , Na-VPA aggravated CER-AP, increasing pancreatic histology scores and biochemical parameters. Transcriptomic and metabolomic analyses showed dysregulated one-carbon metabolism, validated by altered mRNA and protein expression analysis of key rate-limiting enzymes. Molecular docking indicated direct interactions between VPA and several metabolic enzymes. Na-VPA also activated the pancreatic endoplasmic reticulum (ER) stress pathway. In PACs, Na-VPA reduced methionine and SAM levels, while supplementation with methionine or SAM markedly attenuated cell injury; conversely, ethionine exacerbated it. Moreover, SAM supplementation in vivo significantly ameliorated pancreatic damage and biochemical alterations in Na-VPA–exacerbated CER-AP. Conclusion: Na-VPA disrupts one-carbon metabolism, triggering ER stress and acinar cell injury and exacerbating experimental pancreatitis. These findings provide new mechanistic insight into valproate-associated AP and identify metabolic targets for potential prevention or therapy.