Objective To explore the mechanism of lupeol in the treatment of rheumatoid arthritis(RA)based on network pharmacology and molecular docking.Methods The target of lupeol was obtained by Swiss and TCMSP analysis platform,and the RA related target was obtained by searching"rheumatoid arthritis"in GeneCards database,which was transformed into the corresponding standardized gene name by UniProt database.The common targets of lupeol and RA were mapped by R-package,and the cross genes were obtained.The cross genes were introduced into the string database to construct protein protein interactions(PPI)network.The clusterProfiler database was used to analyze the enrichment of GO and KEGG pathways.The binding of lupeol with AR,CASP3 and CCNB1 was evaluated by molecular docking.The RA mouse model was established and the foot volume of each group was measured.HE staining for pathological changes,ELISA kit for detecting mouse serum TNF-α,IL-1β and IL-6 expression levels.The protein expression levels of Bcl-2,Bax,CASP3 and CASP9 were detected by Western blot.Results Forty targets of lupeol,4734 related targets of RA disease and 27 common targets of lupeol RA were obtained.The top three genes of PPI network were AR,CASP3 and CCNB1.291 GO and 20 KEGG pathways were enriched.Molecular docking showed that lupeol had good affinity with AR,CASP3 and CCNB1.The foot volume of the model group was significantly higher than that of the normal control group on the 8th,12th,16th and 20th day(P<0.05).Compared with the model group,the foot volume ofthe lupeol group was significantly lower on the 8th,12th,16th and 20th day(P<0.05),andthat ofthe diclofenac group was significantly lower onthe 12th,16th and 20th day(P<0.05).The HE staining results showed that compared with the model group,the lupine alcohol drug group significantly improved the pathological state.Compared with the model group,the level of TNF-α,IL-1β and IL-6 in serum of mice in the Lupeol drug group decreased(P<0.01).WB results showed that compared with the normal group,the protein expressions of Bax,CASP3 and CASP9 in the model group were significantly decreased(P<0.05),and the protein expression of Bcl-2 was significantly increased(P<0.05).Compared with the model group,the protein expression of Bax,CASP3 and CASP9 in the positive control group and drug group were significantly up-regulated(P<0.05),and the protein expression of Bcl-2 was significantly down regulated(P<0.05).Conclusion Lupeol plays a therapeutic role in RA by regulating Bax,Bcl-2,Casp3 and Casp9 in the p53 signaling pathway.