Objective To explore the improving effect of eicosapentaenoic acid(EPA)on the skeletal muscle insulin resistance in obese rats by regulating the p38 MAPK signaling pathway.Methods Fifty male Wistar rats were randomly divided into the control group,model group,inhibitor group,EPA group and inhibi-tor+EPA group,10 cases in each group.The intervention lasted for 6 weeks.The inhibitor group was given 1 mg/kg p38 MAPK inhibitor SB203580 by gavage.The EPA group was given 70 mg/kg EPA by gavage,the in-hibitor+EPA group was given SB203580+EPA by gavage,and the model group and control group were given equal volume of saline.The levels of fasting blood-glucose,fasting serum insulin,glutathione peroxidase(GSH-Px),superoxide dismutase(SOD)and malondialdehyde(MDA)in the skeletal muscles were deter-mined.The rat insulin resistance degree was evaluated by using the intraperitoneal glucose tolerance test(IPGTT)and insulin tolerance test(ITT).The protein and mRNA expression levels of phosphorylation p38 in the rat skeletal muscle tissues were detected by Western blot and qRT-PCR.Results Compared with the control group,the body weight,epididymal fat wet weight,fasting blood-glucose and insulin levels,IPGTT and ITT blood glucose levels,and MDA content in the model group were significantly increased,the GSH-Px and SOD activities were significantly decreased,and the relative expression levels of p-p38 protein and p38 mRNA expression in skeletal muscle tissues were significantly increased(P＜0.05).Compared with the model group,the body weight and epididymal fat wet weight in the EPA group and inhibitor+EPA group were sig-nificantly decreased,while the fasting blood-glucose,fasting serum insulin,IPGTT and ITT blood glucose lev-els and MDA contents in the inhibitor group and EPA group were significantly decreased,the activities of GSH-Px and SOD were significantly increased,and the relative expression level of p-p38 protein in skeletal muscle tissues was significantly decreased(P＜0.05).However,the expression of p38 mRNA in skeletal muscle tissues had no significant change(P＞0.05).Conclusion EPA alleviates the oxidative stress possibly by inhibiting p38 MAPK signaling pathway,thus improves the skeletal muscle insulin resistance of obese rats.