Octreotide attenuates pancreatic fibrosis through modulation of the HMGB1-Wnt/β-catenin axis in experimental chronic pancreatitis.

Chronic pancreatitis is a progressive fibroinflammatory disease in which activated pancreatic stellate cells and extracellular matrix deposition drive irreversible tissue remodeling. Octreotide has anti-secretory and anti-inflammatory properties, but its anti-fibrotic mechanism remains unclear. To determine whether octreotide attenuates DBTC-induced pancreatic fibrosis through suppression of high-mobility group box 1 (HMGB1) and downstream Wnt/β-catenin signaling. Male Sprague-Dawley rats received dibutyltin dichloride (DBTC, 7 mg/kg) to induce chronic pancreatitis and were assigned to seven groups (n = 10/group) comprising untreated controls, DBTC model rats, and DBTC rats treated with octreotide alone or in combination with HMGB1 overexpression, HMGB1 knockdown, a vector control, or pharmacological Wnt/β-catenin activation. Octreotide was administered at 10 µg/kg/day for 21 days. Pancreatic injury, collagen deposition, stellate cell activation, HMGB1 inflammatory signaling, and Wnt/β-catenin activity were assessed by biochemical assays, histology, hydroxyproline measurement, immunofluorescence, Western blotting, qPCR, and ELISA. DBTC caused weight loss, pancreatic atrophy, elevated amylase/lipase, severe collagen accumulation, and marked increases in collagen I, α-smooth muscle actin (α-SMA), HMGB1, TLR4/RAGE, phospho-NF-κB p65, inflammatory cytokines, active/nuclear β-catenin, Wnt1, phospho-GSK3β, Axin2, c-Myc, and Cyclin D1 (all p < 0.0001 vs. Control). Octreotide substantially reversed these changes, halving fibrosis and hydroxyproline content and suppressing HMGB1 translocation/release (all p < 0.0001 vs. Model). HMGB1 overexpression weakened, whereas HMGB1 knockdown mimicked, octreotide-mediated protection. Wnt activation restored β-catenin activity and fibrosis without significantly changing HMGB1 or TLR4/RAGE/NF-κB signaling (all p > 0.15), a pattern consistent with HMGB1 acting upstream of Wnt/β-catenin. Octreotide limits experimental pancreatic fibrosis by suppressing HMGB1-driven inflammation and downstream Wnt/β-catenin activation, identifying the HMGB1-Wnt/β-catenin axis as a promising anti-fibrotic target.