Liver Kinase B1 in CD11c ⁺ Cells Inhibits Fibrosis in Chronic Pancreatitis via the Oncostatin M Signaling

ABSTRACT Chronic pancreatitis (CP), characterized by irreversible fibrosis, is a high‐risk factor for pancreatic cancer. Current therapeutic strategies remain inadequate. This study identified a significant increase in CD11c ⁺ cells within fibrotic regions of CP patient pancreatic tissues, accompanied by markedly reduced expression of liver kinase B1 (Lkb1) in these cells. Animal experiments confirmed that Lkb1 deletion in CD11c ⁺ cells markedly exacerbated pancreatic fibrosis. Further investigation revealed that Lkb1 deletion in CD11c ⁺ cells drove the differentiation of monocytes into CD11c ⁺ CD206 ⁺ mixed‐phenotype macrophages, leading to their accumulation in fibrotic lesions. The CCL2/CCR2 signaling axis was identified as the key pathway mediating the infiltration of these macrophages. Mechanistically, Lkb1 deletion enhanced STAT3 phosphorylation in CD11c ⁺ CD206 ⁺ macrophages, promoted CCL2 secretion, and thereby promoted more CD11c ⁺ CD206 ⁺ macrophages to infiltrate. CD11c ⁺ CD206 ⁺ macrophages activated pancreatic stellate cells (PSCs) via OSM binding to its receptor OSMR, thereby stimulating CCL2 production of PSCs. This recruits additional monocyte‐derived macrophages to sustain PSC activation and exacerbates extracellular matrix (ECM) deposition. Concurrently, neutralization of OSM suppressed CCL2 secretion from PSCs and markedly attenuated pancreatic fibrosis. This study reveals that Lkb1 deletion in CD11c ⁺ cells exacerbates CP‐associated fibrosis via the OSM and CCL2/CCR2 axis, thereby presenting a potential therapeutic strategy for CP fibrosis.