Objective To investigate the impacts of Morroniside on oxidative stress injury of sciatic nerve in diabetic peripheral neuropathy (DPN) rats.Methods A total of 48 rats were grouped into a control group,DPN group,Morroniside group,Morroniside+Brusatol group,each group consisted of 12 rats.The changes in fasting blood glucose,mechanical pain threshold,thermal pain threshold,and sciatic nerve conduction velocity were detected.Transmission electron microscopy observe the ultrastructural changes of the sciatic nerve.ELISA method detect the levels of interleukin -6 (IL-6),tumor necrosis factor-α(TNF-α),malondialdehyde(MDA),and superoxide dismutase(SOD)activity in the sciatic nerve.Western blot detect nuclear factor erythroid 2 related factor 2 (Nrf2),silent mating-type information regulation 2 homolog 1(SIRT1),and forkhead box class o3(Foxo3)proteins in the sciatic nerve.Results Sciatic nerve myelin in DPN group,Morroniside group,Morroniside+Brusatol group were significantly damaged,fasting blood glucose,heat pain threshold,contents of IL-6,TNF-α and MDA in sciatic nerve were higher than those in control group,mechanical pain threshold,sensory and motor nerve conduction velocity,SOD activity in sciatic nerve and expression of Nrf2,SIRT1 and Foxo3 protein were lower than those in control group(P＜0.05).The ultrastructural damage of sciatic nerve tissue in Morroniside group was improved,and the contents of fasting blood glucose,heat pain threshold,IL-6,TNF-α and MDA in sciatic nerve were lower than those in DPN group.The mechanical pain threshold,sensory and motor nerve conduction velocity,SOD activity and Nrf2,SIRT1,Foxo3 protein expression in sciatic nerve were higher than those in DPN group (P＜0.05).The protective effect of Morroniside was reversed when Brusatol,an Nrf2 inhibitor,was given in addition to Morroniside group.Conclusion Morroniside may improve oxidative stress injury of the sciatic nerve in DPN rats by activating the Nrf2/SIRT1/Foxo3 pathway.