Wu M, Skaug B, Bi X, et al. - Systemic sclerosis (SSc) and healthy control skin biopsies were examined in order to illustrate the role of interferon regulatory factor 7 (IRF7) in dermal fibrosis and SSc pathogenesis. In SSc skin tissue and explanted SSc dermal fibroblasts in comparison with unaffected, matched controls, IRF7 expression was significantly upregulated and activated. Furthermore, in dermal fibroblasts, IRF7 expression was stimulated by IFN-α. Significantly, IRF7 co-immunoprecipitated with Smad3, a key mediator of transforming growth factor (TGF)-β signaling, and IRF7 knockdown decreased profibrotic factors in SSc fibroblasts. In response to bleomycin, IRF7 KO mice exhibited attenuated dermal fibrosis and inflammation vs wild-type mice. Especially, hydroxyproline content, dermal thickness as well as Col1a2, ACTA2 and interleukin-6 mRNA levels were notably attenuated in IRF7 KO mice skin tissue. Moreover, IRF7 KO in TSK/+mice attenuated hydroxyproline content, subcutaneous hypodermal thickness, Col1a2 mRNA as well as α-smooth muscle actin and fibronectin expression. Thus, IRF7 is upregulated in SSc skin, interacts with Smad3 and potentiates TGF-β-mediated fibrosis, and hence, may represent an encouraging therapeutic target in SSc.