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This study examines how sodium valproate (Na\u2010VPA) induces pancreatic injury and contributes to acute pancreatitis (AP).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>Murine pancreatic acinar cells (PACs) were treated with Na\u2010VPA or major VPA metabolites, and cytotoxicity was assessed by spectrofluorometry and confocal imaging. In vivo, C57BL\/6 mice, with or without caerulein\u2010induced pancreatitis (CER\u2010AP), were administered Na\u2010VPA and pancreatic injury was evaluated. Intracellular methionine\u2010cycle metabolites were quantified by LC\u2013MS\/MS, whereas one\u2010carbon metabolism enzyme expression was determined by RT\u2010qPCR and western blotting. AutoDock Vina was employed to predict binding affinities of VPA to key metabolic enzymes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>Na\u2010VPA and its metabolites induced concentration\u2010 and time\u2010dependent PAC death, independent of toxic calcium signalling. In vivo, Na\u2010VPA aggravated CER\u2010AP, increasing pancreatic histology scores and biochemical parameters. Transcriptomic and metabolomic analyses showed dysregulated one\u2010carbon metabolism, validated by altered mRNA and protein expression analysis of key rate\u2010limiting enzymes. Molecular docking indicated direct interactions between VPA and several metabolic enzymes. Na\u2010VPA also activated the pancreatic endoplasmic reticulum (ER) stress pathway. In PACs, Na\u2010VPA reduced methionine and S\u2010adenosylmethionine (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\u2010VPA\u2013exacerbated CER\u2010AP.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>Na\u2010VPA disrupts one\u2010carbon metabolism, triggering ER stress and acinar cell injury and exacerbating experimental pancreatitis. These findings provide new mechanistic insight into valproate\u2010associated AP and identify metabolic targets for potential prevention or therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70429","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:15:09Z","timestamp":1776816909000},"page":"3829-3848","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sodium valproate induces pancreatic injury by disruption of one\u2010carbon metabolism"],"prefix":"10.1111","volume":"183","author":[{"given":"Wenhao","family":"Cai","sequence":"first","affiliation":[{"name":"West China Centre of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China\u2010Liverpool Biomedical Research Centre, West China Hospital Sichuan University  Chengdu Sichuan China"},{"name":"Liverpool Pancreatitis Research Group, Institute of Systems, 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