Apoptotic neuronal death is a common event accounting for neuron loss in ischemic stroke (Cao et al., 2004; Widiapradja et al., 2012; Wang et al., 2014). Therefore, the mechanism of neuronal apoptosis under ischemic conditions has been an important research focus in the past decades. Deregulation of the UPS is believed to be an important contributor to ischemic neuronal injury (Wojcik and Di Napoli, 2004; Doeppner et al., 2016). The E3 ligase Nrdp1 has been recently shown to mediate neuronal apoptosis through reducing BRUCE expression in LPS-induced neuroinflammation (Shen et al., 2015). Our previous study has also demonstrated a role of Nrdp1 in promoting cardiac myocyte apoptosis in experimental I/R (Zhang et al., 2011b). Here our in vivo and in vitro data show that ischemia induces Nrdp1 upregulation in cerebral cortical neurons. Of note, this change is quite rapid and persistent, as Nrdp1 mRNA expression is increased in neurons at 1 h after OGD treatment and remains high at the end of 6-h OGD exposure. Our data that knockdown of Nrdp1 with siRNA reduces OGD-induced cell death/apoptosis and overexpression of Nrdp1 by Ad-Nrdp1 increases neuronal death clearly supports a role of Nrdp1 in ischemic neuronal injury. Moreover, along with Nrdp1 knockdown or overexpression is the inhibition or activation of apoptosis-associated proteins, including caspase-3, PARP-1, Bax/Bcl-2 ratio, further supporting a proapoptotic action of Nrdp1 in OGD-induced neuron injury.