To explore the mechanism of Poria-Atractylodis Macrocephalae Rhizoma drug pair(P-AMR) in the treatment of gastric cancer(GC) by network pharmacology and experimental verification.Methods:Based on oral bioavailability and drug-likeness,the active components were obtained and screened out from Traditional Chinese Medicines Systems Pharmacology(TCMSP).All potential targets of P-AMR were predicted by Swiss Target Prediction database.Targets of GC were collected from the DisGeNET database.The two targets were imported into Cytoscape for intersection,and the core targets were identified by screening out the topological feature values.The protein-protein interaction(PPI) network was constructed.Meanwhile,the Gene Ontology(GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were conducted.The effective targets and pathways were verified by in vitro experiments.Results:A total of 36 active components of P-AMR were confirmed through using the network pharmacology method.The key proteins in the PPI network included mitogen-activated protein kinase(MAPK) 3,prostaglandin-endoperoxide synthase 2(PTGS2),epidermal growth factor receptor(EGFR),MAPK8,MAPK14,peroxisome proliferators-activated receptor-G(PPARG),estrogen receptor 1(ESR1),etc.It was predicted that P-AMR exerted effects on the active components through viral carcinogenesis,phosphoinositide 3-kinase-protein kinase B(PI3K-AKT) signaling pathway,proteoglycans in cancer,and other signaling pathways.Conclusion:P-AMR treats GC in a multi-component,multi-target,and multi-pathway manner,which can participate in the proliferation and invasion of cells by targeting the PI3K-AKT signaling pathway and the protein expression of MAPK3.This study lays a solid foundation for further research on P-AMR in the treatment of GC.