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Background: The mitochondrial unfolded protein response (UPR mt ) is an evolutionarily conserved mitochondrial response that is critical for maintaining mitochondrial and energetic homeostasis under cellular stress after tissue injury and disease. Here, we ask whether UPR mt may be a potential therapeutic target for ischemic stroke., Methods: We performed the middle cerebral artery occlusion and oxygen-glucose deprivation models to mimic ischemic stroke in vivo and in vitro, respectively. Oligomycin and meclizine were used to trigger the UPR mt . We used 2,3,5-triphenyltetrazolium chloride staining, behavioral tests, and Nissl staining to evaluate cerebral injury in vivo. The Cell Counting Kit-8 assay and the Calcein AM Assay Kit were conducted to test cerebral injury in vitro., Results: Inducing UPR mt with oligomycin protected neuronal cultures against oxygen-glucose deprivation. UPR mt could also be triggered with meclizine, and this Food and Drug Administration-approved drug also protected neurons against oxygen-glucose deprivation. Blocking UPR mt with siRNA against activating transcription factor 5 eliminated the neuroprotective effects of meclizine. In a mouse model of focal cerebral ischemia, pretreatment with meclizine was able to induce UPR mt in vivo, which reduced infarction and improved neurological outcomes., Conclusions: These findings suggest that the UPR mt is important in maintaining the survival of neurons facing ischemic/hypoxic stress. The UPR mt mechanism may provide a new therapeutic avenue for ischemic stroke., Competing Interests: Disclosures None.