BACKGROUND: Anti-angiogenesis therapy (AAT) triggers vascular endothelial growth factor (VEGF)-exosomes secretion from tumor-associated endothelial cells (TAECs) for hepatocellular carcinoma (HCC) tubulogenesis and metastasis. Sphingosine-1-phosphate receptor 1 (S1PR1) has been implicated in HCC progression, but it was targeted by microRNA-9 (miR-9) that might mediate the formation of TAECs. This study aims to investigate the role of miR-9 and VEGF-exosomes in S1PR1-mediated HCC progression and resistance to AAT. METHODS: The expression and distribution of miR-9 in HCC tissues were analyzed using qRT-PCR and fluorescence in situ hybridization (FISH). The impact of S1PR1 knockdown on VEGF-exosome uptake, as well as miR-9 and VEGF-exosome-induced epithelial-mesenchymal transition (EMT), migration, and invasion of HCC cells, was assessed by Transwell assays, fluorescence microscopy, and Western blotting. RESULTS: miR-9 expression was significantly upregulated in HCC tissues and selectively localized in CD34⁺ endothelial cells within paracancerous microvessels, suggesting its role in TAEC transformation.miR-9 promoted EMT and enhanced HCC cell migration and invasion, effects that were further potentiated by VEGF-exosomes. S1PR1 knockdown significantly inhibited VEGF-exosome uptake and suppressed miR-9- and VEGF-exosome-induced EMT, migration, and invasion of HCC cells. CONCLUSION: In conclusion, miR-9 facilitates HCC progression by enhancing tumor malignancy and promoting AAT resistance through TAEC-mediated VEGF-exosome secretion. S1PR1 is a critical mediator of this process, and its inhibition represents a potential therapeutic strategy to overcome AAT resistance in HCC.