Taken together, the present study demonstrates that in response to ischemic stimuli, Nrdp1 is upregulated in neurons and contributes to ischemic neuronal death, and this effect may be associated with suppressed adaptive response to hypoxia/ischemia due to accelerated USP8 degradation and HIF-1α destabilization. Therapeutic strategies that target Nrdp1 activation may provide neuroprotection against ischemic brain injury.