Transient cerebral ischemia leads to the endoplasmic reticulum(ER)stress.However,the contributions of ER stress to cerebral ischemia are not clear.To address this issue,the ER stress activators tunicamycin(TM)and thapsigargin(TG)were administered to transient middle cerebral artery occluded(tMCAO)mice and oxygen-glucose deprivation-reperfusion(OGD-Rep)treated neurons.Both TM and TG showed significant protection against ischemia-induced brain injury,as revealed by reduced brain infarct volume and increased glucose uptake rate in ischemic tissue.In OGD-Rep-treated neurons,4-PBA,the ER stress releasor,counteracted the neuronal protection of TM and TG,which also supporting a protective role of ER stress in transient brain ischemia.Knocking down of an ER stress sensor Eif2s1,which is further activated by TM and TG,reduced the OGD-Rep-induced neuronal cell death.In addition,both TM and TG prevented PARK2 loss,promoted its recruitment to mitochondira and activated mitophagy during reperfusion after ischemia.The neuroprotection of TM and TG was reversed by autophagy inhibition(3-methyladenosien and Atg7 knock down)as well as Park2 silencing.The neuroprotection was also diminished in Park2+/-mice.Moreover,Eif2s1 and downstream Atf4 silencing reduced the PARK2 expression,impaired the mitophagy induction and counteracted the neuroprotection.Taken together,the present investigation demonstrates that the ER stress induced by TM and TG protects against the transient ischemic brain injury.The PARK2-mediated mitophagy may be underlying the protection of ER stress.These findings may provide a new strategy to rescue ischemic brains by inducing mitophagy through activating ER stress.