Sodium valproate induces pancreatic injury by disruption of one‐carbon metabolism

BACKGROUND AND PURPOSE: Valproate medications are a leading cause of drug-associated acute pancreatitis. This study examines how sodium valproate (Na-VPA) induces pancreatic injury and contributes to acute pancreatitis (AP). EXPERIMENTAL APPROACH: 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, with or without caerulein-induced pancreatitis (CER-AP), were administered Na-VPA and pancreatic injury was evaluated. Intracellular methionine-cycle metabolites were quantified by LC-MS/MS, whereas one-carbon metabolism enzyme expression was determined by RT-qPCR and western blotting. AutoDock Vina was employed to predict binding affinities of VPA to key metabolic enzymes. KEY RESULTS: Na-VPA and its metabolites induced concentration- and time-dependent PAC death, independent of toxic calcium signalling. 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 S-adenosylmethionine (SAM) levels, whereas 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 AND IMPLICATIONS: 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.