To investigate the mechanism and experimental verification of Morinda citrifolia in the treatment of atherosclerosis (AS) via network pharmacology.CMAUP,TCMSP and SwissADME databases were used to search and screen the active ingredients of M. citrifolia.The AS targets were obtained after setting screening conditions in GeneCards,OMIM,TTD,PharmGKB and Drugbank databases.The protein interaction network (PPI) was constructed using STRING database,and the GO function enrichment analysis and KEGG pathway analysis for intersection targets were performed using R language.The THP-1-derived macrophage model was constructed for in vitro experiment verification.The concentration of M. citrifolia was screened by CCK-8 assay.Oil red O staining and 22-NBD-Cholesterol fluorescence assay were used to detect the intracellular cholesterol in the model cells following the treatment of M. citrifolia.A total of 59 active ingredients,332 targets and 154 targets associated with AS,such as PPARG,MMP9,IL-6 and CCL2,were screened from M. citrifolia.GO function enrichment analysis obtained 2 844 items,and the top 10 items mainly included biological functions such as regulating cell membrane receptors and nuclear receptors.KEGG pathway analysis obtained 182 items,which of the top 20 items primarily contained lipid metabolism and atherosclerosis,peroxisome proliferator-activated receptor (PPAR) signaling pathway,etc.In vitro experiments were performed to validate the appropriate concentration of M. citrifolia (10,20,40 μg/mL) screened by CCK-8 assay firstly.Oil red O staining and 22-NBD-Cholesterol cell fluorescence found that M. citrifolia promoted cholesterol efflux of THP-1-derived macrophages in a dose-dependent manner.Subsequently,RT-PCR and WB assays showed that M. citrifolia activated PPARγ signaling pathway and increased the expression of PPARγ and ATP-binding cassette transporter A1 (ABCA1) significantly.The capability of M. citrifolia to promote cholesterol efflux in THP-1-derived macrophages was decreased dramatically,and the levels of PPARγ and ABCA1 were down-regulated after blunting PPARγ signaling pathway by GW9662,PPARγ inhibitor.Therefore,network pharmacoloty combined with experimental validation in vitro indicated that M. citrifolia could ameliorate atherosclerosis by promoting cholesterol efflux from THP-1-derived macrophages via PPARγ signaling pathway.