This study was designed to investigate the effet of phillyrin(PHI)on sciatic nerve injury in diabetic peripheral neuropathy(DPN)rats based on the high mobility group protein box-1(HMGB1)/advanced glycation end product receptor(RAGE)signal pathway.DPN rat model was established by high fat and high sugar diet combined with injection of streptozotocin(STZ)solution,and the rats were randomly grouped into model group,phillyrin low dose(PHI-L,50 mg/kg)group,phillyrin medium dose(PHI-M,100 mg/kg)group,phillyrin high dose(PHI-H,200 mg/kg)group,and positive drug(mecobalamin,250 μg/kg)group,while another rats with normal diet were treated as the control group.Each group consisted of 10 rats.The conduction velocity of sciatic nerve was measured by BL-420S biological function experiment system;fasting blood glucose(FBG)level was detected by blood glucose meter;the levels of serum HbAlc,IL-6 and TNF-α were measured with ELISA kits;the ultrastructure of sciatic nerve was observed with electron microscope;the levels of ROS,SOD,MDA and MBP in sciatic nerve were detected with commercial kits;the mRNA and protein levels of HMGB1 and RAGE in sciatic nerve were detected by RT-qPCR and Westem blotting.Compared with model group,pathological injury of rats in PHI-M group,PHI-H group and positive drug group was significantly alleviated,the sciatic nerve conduction velocity and MBP/SOD levels were significantly recovered,the levels of FBG,HbAlc,IL-6,TNF-α,and the mRNA and protein levels of ROS,MDA,HMGB1 and RAGE were decreased significantly(P＜0.05).In conclusion,PHI can reduce the inflammatory reaction,reduce DPN in rats,thus plays a therapeutic role,and the mechanism may be related to the inhibition of HMGB1/RAGE signal pathway.