UCP2 Upregulates ACSL3 to Enhance Lipid Droplet Release from Acinar Cells and Modulates the Sirt1/Smad3 Pathway to Promote Macrophage‐to‐Myofibroblast Transition in Chronic Pancreatitis

These findings suggest that UCP2 promotes LD formation and release in acinar cells by upregulating ACSL3 expression. This alteration in the local lipid metabolic environment indirectly drives the MMT process. Additionally, UCP2 may regulate the acetylation of Smad3 through Sirt1, enhancing its nuclear activity and activating the TGF‐β/ Smad3 signaling pathway. This, in turn, promotes fatty acid metabolism, providing energy for macrophage MMT and synergistically inducing pancreatic fibrosis. Abstract Chronic pancreatitis (CP) is a progressive inflammatory disease characterized by pancreatic fibrosis and functional decline. Here, we identify macrophage‐to‐myofibroblast 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‐CoA synthetase long‐chain 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‐β (TGF‐β)/Smad3 signaling to promote macrophage MMT. Macrophage‐specific Sirt1 knockout suppresses both fibrosis and MMT. In conclusion, UCP2 drives CP progression by regulating ACSL3‐mediated LD release in acinar cells and modulating macrophage function through the Sirt1/Smad3 pathway. Targeting UCP2 may represent a promising therapeutic strategy for CP. These findings suggest that UCP2 promotes LD formation and release in acinar cells by upregulating ACSL3 expression. This alteration in the local lipid metabolic environment indirectly drives the MMT process. Additionally, UCP2 may regulate the acetylation of Smad3 through Sirt1, enhancing its nuclear activity and activating the TGF-β/ Smad3 signaling pathway. This, in turn, promotes fatty acid metabolism, providing energy for macrophage MMT and synergistically inducing pancreatic fibrosis. Abstract Chronic pancreatitis (CP) is a progressive inflammatory disease characterized by pancreatic fibrosis and functional decline. Here, we identify macrophage-to-myofibroblast 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-CoA synthetase long-chain 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-β (TGF-β)/Smad3 signaling to promote macrophage MMT. Macrophage-specific Sirt1 knockout suppresses both fibrosis and MMT. In conclusion, UCP2 drives CP progression by regulating ACSL3-mediated LD release in acinar cells and modulating macrophage function through the Sirt1/Smad3 pathway. Targeting UCP2 may represent a promising therapeutic strategy for CP. Advanced Science, Volume 12, Issue 43, November 20, 2025.