〔Abstract〕 Objective To investigate the function and potential mechanism of hepatocellular carcinoma(HCC) cells-derived extracellular nicotinamide phosphoribosyl transferase(eNAMPT) in the angiogenesis of human umbilical vein endothelial cells(HUVEC). Methods The eNAMPT secretion of HCC cells were stimulated by hypoxia treatment and investigated the angiogenesis of HUVEC was investigated by tube formation assays. Transcriptomic RNA sequencing(RNA-seq) analyses of HUVEC under eNAMPT treatment were used to explore the mechanism of the effect of eNAMPT-insulin receptor(INSR) axis on angiogenesis. Western blot was used to detect the effects of eNAMPT-INSR axis on protein expression of HUVEC cells. qRT-PCR was used to detect the influence of eNAMPT-INSR axis on the expression of HUVEC intracellular related target genes. Results ELISA and Western blot results showed that the protein level of eNAMPT in the culture supernatant of HCC cells increased significantly after hypoxia stimulation.In vitroangiogenesis assay results showed that eNAMPT significantly increased the nodules number and total length of tubes in HUVEC. The transcriptome sequencing results of HUVEC showed that eNAMPT, as an insulin analogue, participated in the regulation of biological processes such as cell migration and angiogenesis in HUVEC, and might promote angiogenesis by activating insulin-like signaling pathways. Western blot results showed that the eNAMPT-INSR axis affected p-AKT and p-ERK1/2 protein levels in PI3K-AKT and MAPK-ERK1/2 signaling pathways in HUVEC. qRT-PCR results showed that the eNAMPT-INSR axis affected the expression of angiogenesis related target genes MMP2, MMP9 and VEGF in HUVEC. Conclusion eNAMPT secreted by HCC cells promotes angiogenesis by binding INSR to activate the PI3K-AKT and MAPK-ERK1/2 signaling pathways.