To investigate the expression of the transcription factor PU.1 in mice with pulmonary fibrosis, and investigate its impact on this disease. The pulmonary fibrosis model of C57BL/6 mice was established, and the mice were randomly divided into 10 control group (normal saline intervention), 10 model group (bleomycin intervention), and 10 treatment group (bleomycin + DB1976 intervention). The mice were killed on the 21st day after modeling and samples were collected. Hematoxylin-eosin staining(HE) and Masson staining were used to observe the pathological changes of mouse lung tissue and score pulmonary fibrosis and alveolitis. The expression of PU.1 in alveolar lavage fluid and hydroxyproline(HYP) in serum was detected by ELISA. The expression of PU.1 and macrophage markers Fizz-1, IL-10, CD86 and IL-6 in lung tissues were detected by qPCR. The experimental results were statistically analyzed using SPSS 26.0. The results show that compared with the control group, the lung tissue of mice in the model group and the treatment group show obvious fibrosis changes, collagen deposition is more obvious, and fibrosis score is higher. Compared with the control group, the expressions of PU.1 and HYP in the model group significantly increase(P < 0.05), while the expressions of PU.1 and HYP in the treatment group decrease(P < 0.05), and the scores of alveolar inflammation and fibrosis decrease(P < 0.05). Compared with the control group, M1 and M2 macrophage markers Fizz-1, IL-10, CD86 and IL-6 increase in the model group. Compared with model group, M2 macrophage markers Fizz-1 and IL-10 in lung tissue significantly decrease in treatment group (P <0.05). It is concluded that transcription factor PU.1 may participate in the exacerbation of lung fibrosis by regulating the polarization of M2-type macrophages, and the inhibitor of PU.1 DB1976 can inhibit the expression of PU.1 in the lung, thereby inhibiting the polarization of M2-type macrophages and delaying the process of pulmonary fibrosis.