Abstract: As a new endothelial cell marker, the expression of melanoma cell adhesion molecule, CD146, has been found to be closely related to the progression of tumors and autoimmune diseases. Rheumatoid arthritis（RA） is a systemic autoimmune disease characteri-zed by symmetrical and chronic polyarthritis. Synovial pannus, as a representative pathological product of RA, plays an important role in the occurrence and development of the disease. In order to investigate the differential gene expression and influencing mechanism of CD146 in human unbilical vein endothelial cell line, EAhy.926, under the condition of human rheumatoid arthritis fibroblast like synovial cell（HFLS-RA） culture medium, we suppressed the expression of CD146 in EAhy.926 cells by using lentivirus mediated RNA interference technology. We cultivated and extracted the supernatant of HFLS-RA to prepare conditioned culture medium. And then, we cultivated the transfected EAhy.926 cells in HFLS-RA conditioned medium for 24 h to construct a RA injury model, and performed transcriptome sequencing on it to screen differentially expressed genes（DEGs）. Through GO and KEGG pathway analysis, we explored the relevant signaling pathways and biological processes involved in CD146 regulated DEGs. The results showed that compared with the control group cells, EAhy.926 cells with CD146 knockdown in HFLS-RA conditioned medium had 341 DEGs, including 173 upregulated genes and 168 downregulated genes; GO analysis and KEGG pathway analysis revealed that differentially expressed genes were mainly enriched in the Wnt signaling pathway, PPAR signaling pathway, inflammatory mediator regulation of TRP channels, and adipocyte cytokine signaling pathway, and were involved in biological processes such as cell adhesion, cell movement, cell localization, and cysteine biosynthesis process. This study found that at the transcriptome level CD146 may affect EAhy.926 through multiple key signaling pathways and genes under the condition of HFLS-RA conditioned medium. This study provided a theoretical basis for exploring the role and mechanism of CD146 in synovial angiogenesis in rheumatoid arthritis.