Objective To investigate the effects of methylprednisolone on STAT3-ERK1/2 signaling pathway in lipopolysaccharide (LPS)-induced acute lung injury (ALI).Methods The C57BL/6J male mice (8-week-old) were randomly(random number) divided into 4 groups:control group (control),LPS-induced endotoxemia model (LPS),only methylprednisolone (MP) administration group (MP),and intervention group with 2 mg/kg MP (LPS+MP) (n=8 per group).The wet/dry (W/D) weight ratio of lung tissue,lung pathology by hematoxylin & eosin (HE) staining,serum and mRNA levels of TNF-α and IL-6 in lungs were determined.The protein levels of p-STAT3 and p-ERK1/2 in lungs were detected by Western blot.Statistical analyses were performed using One-way analysis of variance test to compare among multiple groups.Results (1)MP treatment significantly decreased the lung W/D weight ratio compared with the LPS group[(3.01±0.84) vs(3.87±0.17),P =0.038];(2) The histopathological lesions of the lung were improved in the LPS+MP group compared with the LPS group accompanied with reduced inflammatory cell infiltration and attenuated the alveolar wall thickening;(3) The serum levels of TNF-α and IL-6 in the LPS+MP group was significantly decreased compared with the LPS group[(3.17±l.64) pg/mL vs (6.61±1.27) pg/mL,P =0.003;(1.42±0.35) pg/mL vs (3.80±1.35) pg/mL,P =0.008,respectively],and the mRNA levels of TNF-α and IL-6 in the LPS+MP group were significantly lower than those of the LPS group [(5.10±0.81) vs (12.2±5.05),P =0.03;(1.62±1.00) vs (11.12±6.56),P=0.026;respectively];(4)MP therapy significantly inhibited P-STAT3 and P-ERK1/2 protein levels [(0.26±0.05) vs (0.86±0.06),P ＜0.001,(0.24±0.02) vs (1.34±0.32),P ＜ 0.001].Conclusions Methylprednisolone protects LPS-induced acute lung injury possibly via suppressing STAT3-ERK1/2 signaling pathway and reducing TNF-α and IL-6 expression.