Chaiqin chengqi decoction alleviates acute pancreatitis by targeting gasdermin D-mediated pyroptosis.

Ethnopharmacological Relevance: Acute pancreatitis (AP) is an acute inflammatory condition of pancreas with high morbidity and mortality, which has no effective medical treatment. Chaiqin chengqi decoction (CQCQD) has been clinically used for AP for many years in China. However, the underlying mechanisms are still unknown.

Aim Of The Study: To investigate the mechanism of CQCQD on gasdermin D (GSDMD) -mediated pyroptosis in AP.

Materials And Methods: In this study, network pharmacology was used to screen the potential mechanism of CQCQD protecting against AP and then we focused to investigate the mechanism of CQCQD on GSDMD mediated pyroptosis. Mouse models of AP were conducted by caerulein and L-arginine. In order to clarify the mechanism of CQCQD, two kinds of GSDMD gene knockout mice (Gsdmd and Pdx1Gsdmd) were applied. And the potential interaction between the main components of CQCQD and GSDMD was explored by molecular docking.

Results: In the caerulein-induced AP model, CQCQD ameliorated pancreatic pathological injury, attenuated systemic inflammation and serum enzymatic levers. Moreover, network pharmacology analysis showed GSDMD mediated pyroptosis was one of the core targets of CQCQD protecting against AP. Additionally, CQCQD appreciably decreased the levels of pyroptosis-related proteins N-terminal GSDMD, nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3, and cleaved Caspase-1. Furthermore, the protective effect of CQCQD was neutralized in Gsdmd and Pdx1Gsdmd mice in caerulein-induced AP. In addition, we found that CQCQD protects pancreatic tissue from damage and pancreatitis-associated lung injury in the L-arginine-induced mouse model. Moreover, all of the main components of CQCQD possessed binding activity with GSDMD by molecular docking. Seventeen components bound with the human GSDMD Cys191 successfully, which is important for GSDMD pore formation. Among the components, rhein possessed the highest binding activity.

Conclusion: CQCQD could reduce pancreatic necrosis and inflammatory response via inhibiting GSDMD-mediated pyroptosis in acinar cells of AP. Rhein may be the key active ingredient of CQCQD in suppressing pyroptosis.