OBJECTIVE：To study the protective effects of Lespedeza cunea ta extract on glutamate-induced hippocampal cells HT22 injury of mice and its possible mechanism based on Nrf 2/HO-1 signaling pathway. METHODS ：Using glutamate （5 mmol/L） to extablish the injury model of HT 22 cells. Using water soluble vitamin E as positive control （50 µmol/L），MTT assay was used to detect the effects of 0（blank control ），25，50，100 µg/mL petroleum ether extract ，dichloromethane extract ，ethyl acetate extract of L. cuneata on the proliferation of glutamate-induced injury cellsafter pretreated for 12 h. Using water soluble vitamin E as positive control （50 µmol/L），DCFH-DA assay was used to detect the effects of 0（blank control ），25，50，100 µg/mL L. cuneata dichloromethane extract on the level of active oxygen （ROS）in glutamate-induced injury cells after pretreated with 12 h. Using HO-1 agonist CoPP as positive control ，Western blotting method was used to detect the effects of 0（blank control ），25，50，100 µg/mL L. cuneata dichloromethane extract on the protein expression of HO- 1 after treated for 24 h. Western blotting method （treated for 0.5，1，1.5 h）and immunofluorescence staining （treated for 1 h）were used to detect the effects of 100 µg/mL L. cuneata dichloromethane extract on protein expression of Nrf 2 inside and outside the nucleus. After HO-1 gene was silenced by small interfering RNA （Si RNA ）transfection technology ，the effects of 100 µg/mL L. cuneata dichloromethane extract on the survival rates of glutamate-induced injury cells and the level of ROS were detected. RESULTS ：Compared with blank control ，50， 100 µg/mL L. cuneata dichloromethane extract could significantly improve the survival rate of glutamate-induced injury cells （P＜ 0.05），while reduced the level of ROS （P＜0.05）. 25，50， 100 µg/mL L. cuneata dichloromethane extract could increase the protein expression of HO- 1 in cells（P＜0.05），while 100 com µg/mL L. cuneata dichloromethane extract could significantly decrease the protein le vel of Nrf 2 in cytoplasm and increasethat in nucleus （P＜0.05）. After HO-1 gene silencing ，the effects of L. cuneata dichloromethane extract on the proliferation promotion of glutamate-induced injury cells and the reduction of ROS level were reversed （P＜0.05）. CONCLUSIONS ：L. cuneata dichloromethane extract can protect HT 22 cells against injury induced by glutamate through activating Nrf 2 pathway，inducing HO- 1 expression.