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Here, we identify macrophage\u2010to\u2010myofibroblast transition (MMT) as a novel feature of CP and investigate the role of mitochondrial uncoupling protein 2 (UCP2) in this process. Using mouse models, human pancreatic specimens, and cell lines, we show that UCP2 is markedly upregulated in CP, primarily in acinar cells. UCP2 knockout reduces MMT and alleviates fibrosis, whereas macrophage depletion reverses this protective effect, confirming the central role of MMT. Metabolomic profiling reveals that UCP2 knockout alters lipid metabolism by downregulating acyl\u2010CoA synthetase long\u2010chain family member 3 (ACSL3) and reducing lipid droplet (LD) release in acinar cells. Mechanistically, UCP2 upregulation increases silent information regulator 1 (Sirt1) expression, enhances Smad3 phosphorylation and nuclear translocation, and activates transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2)\/Smad3 signaling to promote macrophage MMT. Macrophage\u2010specific Sirt1 knockout suppresses both fibrosis and MMT. In conclusion, UCP2 drives CP progression by regulating ACSL3\u2010mediated LD release in acinar cells and modulating macrophage function through the Sirt1\/Smad3 pathway. Targeting UCP2 may represent a promising therapeutic strategy for CP.<\/jats:p>","DOI":"10.1002\/advs.202412571","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T10:38:34Z","timestamp":1756377514000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["UCP2 Upregulates ACSL3 to Enhance Lipid Droplet Release from Acinar Cells and Modulates the Sirt1\/Smad3 Pathway to Promote Macrophage\u2010to\u2010Myofibroblast Transition in Chronic Pancreatitis"],"prefix":"10.1002","volume":"12","author":[{"given":"Kunpeng","family":"Wang","sequence":"first","affiliation":[{"name":"Department of General Surgery Renmin Hospital of Wuhan University Wuhan 430060 China"},{"name":"General Surgery Laboratory Renmin Hospital of Wuhan University Wuhan 430060 China"},{"name":"Hubei Key Laboratory of Digestive System Disease Wuhan 430060 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