Abstract: Objective:To investigate the inhibitory effects of halofuginone on radiation-induced pulmonary injury and to explore the therapeutic mechanism of this drug. Methods:A total of 72healthy female C 57BL/6 mice were randomized into4 groups, namely, control, irradiation, halofuginone, and irradiation plus halofuginone groups, with 18mice in each group. No treatment was performed in the control group. In the halofuginone group, the halofuginone lavage was conducted once a day, with a continuous course treatment for a month or until sacrifice of the mice. In the therapeutic alliance group, the treatment mode was the same as that in the halofuginone group. Then, a 6MV-X ray single fraction irradiation was performed after the completion of a15-day intragastric administration. At 24h, 1 week,2 weeks, 4 weeks, 12weeks, and 20weeks after the irradiation, 3 mice from each group were randomly sacrificed, and total lung tissues were harvested. The lung was dissected to prepare pathological sections. The sections were stained with hematoxylin and eosin staining (H&E) to explore morphologic changes. The protein and mRNA expression levels of TGF- β 1 were analyzed by a combi-nation of immunohistochemistry and polymerase chain reaction. The level of hydroxyproline was also measured.Results: The out-comes of H&E staining showed that halofuginone markedly ameliorated the acute pulmonary inflammation and fibrosis induced by irra -diation. The combination group had a lower level of hydroxyproline than the irradiation group, with statistically significant differences at 20weeks after irradiation (P=0.037). The protein and mRNA expression levels of TGF-β 1 were higher in the irradiation and combi-nation groups than in the control group and (or) halofuginone group at different time points (P<0.05). The combination group had lower TGF-β 1 protein expression than the irradiation group at different time points, with statistically significant differences at 2, 4, 12, and 20 weeks after the irradiation (P<0.05). Meanwhile, TGF-β 1 mRNA level was lower in the combination group than in the irradiation group only at 4 and 12weeks after the irradiation (P<0.05). Conclusion:Halofuginone can ameliorate the irradiation-induced lung inflammation and fibrosis probably by inhibiting the radiation-induced TGF- β 1 expression. Therefore, halofugione is expected to be a therapeutic drug for preventing irradiation injury of the lung.