Here, we first revealed the upregulation of VGLL3 in RA synovium and further demonstrated that VGLL3 drove the IRF3-induced IFN-β secretion in RA-FLS by inhibiting WWTR1 expression and subsequently promoted type I IFN signature expression through autocrine IFN-β signaling. This evidence concerns the gene IFNB1 and rheumatoid arthritis.