Published online Dec 5, 2025. doi: 10.4292/wjgpt.v16.i4.111977
Revised: August 13, 2025
Accepted: November 13, 2025
Published online: December 5, 2025
Processing time: 144 Days and 2.5 Hours
Chronic pancreatitis is a progressive, debilitating condition with no standardized treatment. Pirfenidone and simvastatin are potential therapeutic agents that exert anti-inflammatory and antifibrotic effects on pancreatic acinar cells.
To evaluate the synergistic effects of pirfenidone and simvastatin in an L-arginine-induced chronic pancreatitis model in mice.
A preclinical, 7-week study was performed using a mouse model of L-arginine-induced chronic pancreatitis. The mice were divided into five groups: Normal control; model control; pirfenidone-treated; simvastatin-treated; and combination-treated (pirfenidone + simvastatin). Treatment started in week 3 after disease induction. Mice were euthanized at weeks 4 and 7 for blood collection and tissue sampling for histological and biomarker analysis, including cytokines, oxidative stress markers, and indicators of fibrosis.
Combination therapy significantly reduced levels of tumor necrosis factor-alpha (11.10 ± 1.57 pg/mL vs 24.30 ± 2.00 pg/mL), interleukin-10 (11.70 ± 1.12 pg/mL vs 19.60 ± 1.27 pg/mL), and transforming growth factor-beta 1 (236.13 ± 6.95 pg/mL vs 550.52 ± 42.18 pg/mL) at week 7 (P < 0.05 vs model control). The glutathione peroxidase 1 level increased across all treatment groups, significantly in the pirfenidone-treated group (5.47 ± 0.34 IU/mL vs 5.04 ± 0.43 IU/mL; P < 0.05). Lipid peroxidation levels decreased significantly in the combination-treated group (111.87 ± 7.36 mmol/mL vs 192.85 ± 0.98 mmol/mL; P < 0.05). Histology revealed extensive collagen accumulation and damage to the exocrine pancreas in the model control group (vs treatment groups). Combination therapy elicited the least damage.
Combination of pirfenidone and simvastatin demonstrated a synergistic therapeutic effect in reducing inflammation, fibrosis, and oxidative stress in an L-arginine-induced chronic pancreatitis mouse model, suggesting promise for chronic pancreatitis management.
Core Tip: Combination therapy with pirfenidone and simvastatin significantly attenuated inflammation, fibrosis, and oxidative stress in an L-arginine-induced mouse model of chronic pancreatitis. The synergistic action led to reduced tumor necrosis factor-alpha, transforming growth factor-beta 1, and lipid peroxidation levels, along with a preservation of pancreatic tissue architecture. The combination therapy also enhanced antioxidant defense as evidenced by increased glutathione peroxidase 1 activity, indicating mitigation of oxidative damage. These findings highlighted a promising strategy targeting multiple pathological pathways, namely inflammatory, fibrotic, and oxidative stress mechanisms, and supported further evaluation of this combination in translational and clinical studies for chronic pancreatitis.