Silencing IFIT3 suppresses the EGFR/VEGF pathway and modulates SOCS1 to attenuate skin fibrosis in systemic sclerosis

Systemic sclerosis (SSc) is a life-threatening autoimmune disease characterized by progressive skin and organ fibrosis. Although interferon signaling is dysregulated in SSc, the role of interferon-induced proteins like IFIT3 in the skin fibrosis of SSC remains unclear. Here, we demonstrate that IFIT3 expression is significantly elevated ( p  < 0.01) in SSc fibroblasts and promotes fibrosis via SOCS1-dependent activation of the EGFR/VEGF axis. Silencing IFIT3 upregulated SOCS1 ( p  < 0.05), suppressed EGFR/VEGF ( p  < 0.01), and inhibited fibroblast proliferation/migration ( p  < 0.01). In a bleomycin-induced SSc model, IFIT3 knockdown ameliorated skin/lung collagen deposition and fibrosis ( p  < 0.05). Our findings reveal a novel mechanism whereby IFIT3 regulates EGFR and VEGF through down-regulating SOCS1 in SSc fibrosis, identifying IFIT3 as a novel therapeutic target for SSc.