Our study revealed that VGLL3 predominantly regulated ISGs (especially type I ISGs) in RA-FLS, including STAT1, TNFSF13B, MX1, OAS1, IFI6, IFIT1, ISG15, LY6E, IFITM3, IRF7, and RSAD2. Here, ISG15 is linked to rheumatoid arthritis.