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Abstract Background Radiation-induced lung toxicity (RILT) is a severe complication of radiotherapy in patients with thoracic tumors. Through proteomics, we have previously identified vitronectin (VTN) as a potential biomarker for patients with lung toxicity of grade ≥ 2 radiation. Herein, we explored the molecular mechanism of VTN in the process of RILT. Methods In this study, lentivirus encoding for VTN and VTN-specific siRNA were constructed and transfected into the cultured fibroblasts and C57BL mice. Real-time PCR, western blot and ELISA were used to examine expression of collagens and several potential proteins involved in lung fibrosis. Hematoxylin–eosin and immunohistochemical staining were used to assess the fibrosis scores of lung tissue from mice received irradiation. Results The expression of VTN was up-regulated by irradiation. The change trend of collagens, TGF-β expression and p-ERK, p-AKT, and p-JNK expression levels were positively related with VTN mRNA level. Furthermore, overexpression of VTN significantly increased the expression level of α-SMA, as well as the degree of lung fibrosis in mice at 8 and 12 weeks post-irradiation. By contrast, siRNA VTN induced opposite results both in vitro and in vivo. Conclusions VTN played a positive role in the lung fibrosis of RILT, possibly through modulation of fibrosis regulatory pathways and up-regulating the expression levels of fibrosis-related genes. Taken together, all the results suggested that VTN had a novel therapeutic potential for the treatment of RILT.