Abstract: Objective　To investigate the effect and mechanism of fenofibrate (Fen) on acute lung injury (ALI). Methods　(1) In vivo experiment:thirty male C57BL/6 mice were divided into 6 groups by random number table method including the normal group, the model group (LPS group), the positive drug (dexamethasone) group, and the fenofibrate (Fen) low, medium and high dose (20, 40 and 80 mg/kg) groups. After 12 h of administration, the rats were sacrificed, wet/dry ratio of lung tissue was recorded. The contents of TNF-α, IL-1β and IL-6 in lung tissue were detected by enzyme linked immunosorbent assay (ELISA). The total protein content and immune cell number in the bronchoalveolar larage fluid (BALF) were determined by BCA colorimetry and Wright-Giemsa staining. Hematoxylin-eosin (HE) staining was used to observe lung lesions and pathological scores. Western blotting was used to detect the expressions of B-cell lymphoma-2 (Bcl-2), bcl-2-Associated X (Bax), c-Jun N-terminal kinase (JNK) and phosphorylated c-Jun N-terminal kinase (p-JNK) in lung tissues. (2) In vitro experiment: the experiment consisted of 7 groups including the control group, the LPS (10 mg/L) group, the LPS+Fen (5 μmol/L) group, the LPS+Fen (10 μmol/L) group, the LPS+Fen (20 μmol/L) group. A549 cells were treated with LPS (10 mg/L) and Fen (5, 10 and 20 µmol/L) for 12 h, respectively. DCFH-DA, Annexin V-FITC/PI and Western blot assay were used to detect effects of Fen on ROS levels, apoptosis and expression of apoptosis-related proteins Bcl-2, Bax and p-JNK in A549 cells. After LPS (10 mg/L) +Fen (20 μmol/L) treatment, H2O2 (100 μmol/L) was added to observe the changes of ROS, apoptosis rate and expression of apoptosis-related proteins Bcl-2 and Bax. In addition, LPS (10 mg/L) and Fen (20 μmol/L) were treated and JNK agonist anisomycin (3 μmol/L) was added to observe the expression changes of Bcl-2 and Bax. Results　(1) Compared with the normal group, the lung wet-dry ratio, lung histopathological score, the contents of TNF-α, IL-1β, IL-6, the number of total proteins and immune cells in alveolar lavage fluid, p-JNK and Bax expression were significantly increased in the model group, and the expression of Bcl-2 was significantly decreased. Compared with the model group, the changes of above indexes were significantly reversed in the Fen low, medium and high dose groups (20, 40, 80 mg/kg). (2) Fenofibrate significantly reduced ROS content, decreased apoptosis rate, inhibited p-JNK and Bax expression and promoted Bcl-2 expression in LPS-induced A549 cells, which were reversed by H2O2 treatment. Up-regulation of Bcl-2 and down-regulation of Bax expression induced by Fen in LPS-induced A549 cells were reversed by anisomycin treatment. Conclusion　Fenofibrate inhibits apoptosis through ROS/JNK signaling, so as to reduce ALI.