Integrated LC-MS/MS profiling, network pharmacology and experimental validation reveal inhibition of the IL-6/JAK2/STAT3 pathway by Shenqi Compound in comorbid chronic pancreatitis and type 2 diabetes mellitus.
TL;DR
SQC treatment is associated with the suppression of the IL-6/JAK2/STAT3 pathway, accompanied by reduced inflammation, decreased fibrosis, and improvements in both exocrine and endocrine functions in model mice, suggesting that the formula potentially acts as a holistic regulator.
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Shenqi Compound (SQC) is effective in treating type 2 diabetes mellitus (T2DM). Preliminary clinical observations suggest that it may also improve pancreatic fibrosis in T2DM patients with comorbid chronic pancreatitis (CP), which prompted this mechanistic study.
Aims
OF THE STUDY This study aimed to reveal the multi-component, multi-target, and multi-pathway mechanism of SQC in pancreatic exocrine and endocrine diseases by integrating LC-MS/MS, network pharmacology, molecular docking, molecular dynamics simulation, and in vivo validation.
Materials And Methods
Active components and targets of SQC were screened using network pharmacology and LC-MS/MS. Molecular docking and dynamics simulation validated key component target binding. A mouse model of comorbid CP and T2DM was established by feeding a 60% high-fat diet for six weeks, combined with intraperitoneal injection of caerulein (50 μg/kg, six times daily, three days per week, for six weeks) followed by streptozotocin (50 mg/kg daily for five consecutive days). Pancreatic function, histopathology, and protein expression were assessed.
Results
Network pharmacology identified 145 active components acting on 242 targets, with IL-6, JAK2, and STAT3 as core targets. Quercetin, kaempferol, and luteolin showed good binding to these proteins. The luteolin JAK2 complex remained stable over 100 ns. In animal experiments, SQC improved body weight and food intake, lowered fasting blood glucose, and increased serum glucagon, insulin, lipase, amylase, and fecal elastase 1. SQC also reduced pancreatic IL-6 and TNF-α, alleviated pathological damage and fibrosis, downregulated gp130 and JAK2/STAT3 phosphorylation, and upregulated SOCS3.
Conclusion
SQC treatment is associated with the suppression of the IL-6/JAK2/STAT3 pathway, accompanied by reduced inflammation, decreased fibrosis, and improvements in both exocrine and endocrine functions in model mice. These findings suggest that the formula potentially acts as a holistic regulator, though the direct causal relationship requires further verification through pathway blockade or genetic ablation.