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Metabolic dysfunction\u2010associated steatohepatitis (MASH) has become the leading cause of chronic liver disease, but there has been no approved pharmacotherapy to date. <jats:italic>Methods<\/jats:italic>. We used a network analysis approach to delineate protein\u2010protein interactions that contribute to the transition from steatosis to MASH, in order to identify and target this transition as a potential pharmacotherapeutic strategy. Acyl\u2010CoA thioesterase 1 (ACOT1) was identified as a critical node in the protein\u2010protein interaction (PPI) network of the transition from steatosis to MASH in patient samples. ACOT1 overexpression and silencing effects were tested <jats:italic>in vivo<\/jats:italic> on C57BL\/6 mice exposed to high\u2010fat diet (HFD) and inoculated with an adenoviral system to modulate <jats:italic>ACOT1<\/jats:italic> expression. Transcriptomic and untargeted lipidomic profiles were performed on the mouse livers. <jats:italic>Results<\/jats:italic>. ACOT1 expression was 3\u2010fold higher in MASH as compared to steatosis. In patient samples, <jats:italic>ACOT1<\/jats:italic> was significantly correlated with the severity of MASH as reflected by the nonalcoholic fatty liver disease score. Experimental validation showed that downregulation of ACOT1 resulted in decreased lipid accumulation and prevention of MASH <jats:italic>in vivo<\/jats:italic>. Conversely, upregulation of ACOT1 via an adenoviral vector resulted in development of MASH, whereas control mice only developed steatosis. Lipidomic analysis revealed glycerophospholipids to be especially abundant in MASH accelerated by ACOT1 upregulation. <jats:italic>Conclusion<\/jats:italic>. These results suggest that ACOT1 contributes to the transition from steatosis to MASH through modulation of glycerophospholipid accumulation and its potential as a novel therapeutic target in MASH. This trial is registered with <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/classic.clinicaltrials.gov\/ct2\/show\/NCT02148471\">NCT02148471<\/jats:ext-link>.<\/jats:p>","DOI":"10.1155\/2024\/5560676","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T19:20:06Z","timestamp":1720725606000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Acyl\u2010CoA Thioesterase 1 Contributes to Transition of Steatosis to Metabolic\u2010Associated 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