〔Abstract〕 Objective To investigate the effect of naringenin(NAR) on mechanical ventilation-induced lung injury(VILI) and its possible mechanism. Methods Sixty C57 BL/6 mice were divided into sham operation group(sham), mechanical ventilator model group(Model), naringenin low-dose group(L-NAR, 15 mg/kg) and naringenin high-dose group(H-NAR, 60 mg/kg), with 15 mice in each group. The drug was administered orally 7 days before the modeling, once a day for 7 consecutive days. Then the VILI model was established by mechanical spring flow ventilation, the oxygenation index(OI) was determined by blood collection with internal carotid artery. Mice were sacrificed after 4 h mechanical ventilation and bronchoalveolar lavage fluid(BALF) was collected. The contents of TNF-α, IL-1β and IL-18 in BALF were determined by ELISA. Lung tissue was taken and the wet/dry ratio(W/D) of lung tissue was determined. Histopathological changes were observed by HE staining and scored. The mRNA and protein expression levels ofNLRP3、ASC and Caspase-1 were detected in macrophages by RT-PCR and Western blot, respectively. Results Compared with the sham group, the Model group had severe lung tissue injury, the lung histopathological score, W/D value, the content of TNF-α, IL-1β and IL-18 in BALF, and the mRNA and protein expression levels ofNLRP3,ASC and Caspase-1 in lung tissue increased(P<0.01), while the OI value decreased(P<0.01). Compared with the Model group, the degree of lung tissue injury improved in the H-NAR group, the lung histopathological score, W/D value, the content of TNF-α, IL-1β and IL-18 in BALF, and the mRNA and protein expression levels of NLRP3, ASC and Caspase-1 in lung tissue decreased(P<0.01), the OI value increased(P<0.01), However, there was no significant difference in relevant indicators between the L-NAR group and the Model group. Conclusion NAR pretreatment reduced VILI in mice, and the mechanism may be related to the inhibition of NLRP3 inflammasome activation.