OBJECTIVE  To investigate the role and mechanism of the ethanol extract of Cocculus orbiculatus in the intervention of L-arginine-induced acute pancreatitis in rats, using a combination of network pharmacology and experimental validation.

METHODS  The main chemical constituents of the ethanol extract of Cocculus orbiculatus were identified through a comprehensive literature search. Various databases were utilized to analyze and predict the pharmacological mechanisms of extract of Cocculus orbiculatus. Simultaneously, mice were randomly divided into four groups, each consisting of 8 mice: blank control group, model group, low and high-dose extract of Cocculus orbiculatus group (150, 300 mg·kg⁻¹). The therapeutic efficacy and pharmacological mechanisms of extract of Cocculus orbiculatus in the intervention of L-arginine-induced acute pancreatitis were assessed through gross specimens, histopathological examination, biochemical analysis, and molecular biology assays.

RESULTS  The primary active components of the ethanol extract of Cocculus orbiculatus responsible for the modulation of acute pancreatitis were determined to be magnolol, honokiol, and houttuynine. Key target proteins, including SRC, MAKP8, STAT3, AKT1, among others, were identified. GO functional enrichment analysis demonstrated significant enrichment of 2093 GO terms (P<0.05), comprising 1799biological process terms, 176 cellular component terms, and 118 molecular function terms. KEGG pathway enrichment analysis demonstrated that the ethanol extract of Cocculus orbiculatus primarily exerted its therapeutic effects on acute pancreatitis through the modulation of the NOD-like receptor signaling pathway and the PI3K-Akt signaling pathway. In animal experiments, compared with the model group, the group receiving extract of Cocculus orbiculatus intervention showed reduced pancreatic scores and pancreatic lengths, along with improved cellular inflammation infiltration observed through histopathological examination. Additionally, ethanol extract of Cocculus orbiculatus downregulated the expression level of NLRP3, inhibited the activation of Caspase-1 and the generation of GSDMD-N, and suppressed the release of inflammatory substances (IL-1β, IL-18), thereby effectively inhibiting pyroptosis.

CONCLUSION  The ethanol extract of Cocculus orbiculatus exhibits therapeutic effects in mice with L-arginine-induced acute pancreatitis by modulating cell pyroptosis and inhibiting the release of inflammatory factors.