Abstract: Abstract: Background Radiation-induced lung injury represents the most critical dose-limiting toxicity in radiotherapy for thoracic malignancies. As a late-stage adverse effect, radiation-induced lung fibrosis currently lacks effective treatment options. Objective To investigate the therapeutic effects of surufatinib on radiation-induced lung fibrosis and the underlying mechanisms. Methods 10 6-8-week-old male C57BL/6 mice were randomly divided into a control group and a treatment group, with 5 mice in each group. The treatment group received surufatinib (dosage: 20 mg/kg; concentration: 4 mg/mL) via oral gavage for 4 weeks, while the control group was administered an equivalent volume of saline using the same method. The toxicity of surufatinib was evaluated through H&E staining of tissues and serum biochemical analyses, including creatinine (CRE), blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine kinase-MB (CK-MB). Thirty male specific pathogen free-grade C57BL/6 mice at 6 - 8 weeks of age were randomly divided into a normal control group, an irradiation group, and a irradiation + surufatinib group. A mouse model of radiation-induced lung fibrosis was established with thoracic γ radiation at a single dose of 20 Gy. Irradiation + surufatinib group mice received surufatinib via oral gavage (20 mg/kg/day for 4 consecutive weeks; concentration: 4 mg/mL) starting at week 8 post-irradiation. Twelve weeks after irradiation, the degree of lung fibrosis was evaluated using lung coefficient, H&E staining and Masson staining, and the expression levels of α-SMA and collagen I were detected using immunohistochemical staining. Total proteins were extracted from lung tissues, and the expression levels of Arg-1 and YM-1 were detected by Western blot. In vitro experiments, RAW264.7 cells and BMDMs were treated with surufatinib after the administration of IL-4 and IL-10. The expression levels of Arg-1 and YM-1 were determine by Western blot. Results In vivo experiments, no signs of toxicity were observed in mice treated with surufatinib according to histological analysis and biochemistry test. Histopathological analysis (H&E staining, Masson staining, and immunohistochemical staining) demonstrated that at 12 weeks post-irradiation, the irradiation group exhibited substantial collagen fiber deposition in lung tissues, accompanied by elevated lung index, α-SMA, and Collagen I expression. These pathological alterations were significantly ameliorated in the irradiation + surufatinib group (P＜0.001). The expression levels of Arg-1 and YM-1 were down-regulated in the irradiation + surufatinib group(P＜0.05). The CCK-8 assay results indicated that both types of macrophages exhibited a decrease in cell viability at a concentration of 4 μM. Experiments in vitro further confirmed that surufatinib inhibited the M2 polarization of macrophages induced by IL-4 and IL-10.Conclusion Surufatinib has a therapeutic effect on radiation-induced lung fibrosis in mice by inhibiting the polarization of macrophages to the M2 phenotype.