Chaihu Guizhi Ganjiang Decoction ameliorates chronic pancreatitis by modulating the SK1/S1P signaling pathway

Abstract

Chronic pancreatitis (CP) is a progressive disease characterized by injury on pancreatic acinar cells (PACs), ongoing fibrosis, and gradual loss of exocrine and endocrine functions. Sphingosine kinase 1 (SK1) expression is elevated in injured PACs, and its metabolite sphingosine-1-phosphate (S1P) promotes the activation of pancreatic stellate cell (PSC) through autophagy and pyroptosis. Chaihu Guizhi Ganjiang Decoction (CGGD), a traditional Chinese medicine is widely used in the clinical treatment of digestive diseases. However, whether CCGD affects the SK1/S1P axis and relieves pancreatic damage through this pathway remains unknown. In this study, CP rats were treated with CGGD, individually or in combination with S1P and SKI-178 for four weeks to assess the effect of CGGD on pancreatic injury, fibrosis, autophagy and pyroptosis. The results showed that SK1, S1P and S1PR2 levels were increased in the pancreatic tissues of CP rats, while CGGD reduced these levels. Treatment with S1P exacerbated histological damage, promoted fibrosis, accelerated autophagy, and induced pyroptosis. Conversely, SKI-178 suppressed these effects. Notably, CGGD mitigated histological damage, decreased serum amylase and lipase levels, and alleviated pancreatic fibrosis induced by S1P. Furthermore, CGGD downregulated autophagy and pyroptosis induced by S1P, exhibiting an effect comparable to SKI-178 in CP. In conclusion, CGGD ameliorates pancreatic damage by reducing fibrosis, inhibiting autophagy, and suppressing pyroptosis through the SK1/S1P axis.

Graphical Abstract