USP8 can protect HIF-1α from degradation mediated by E3 ubiquitin ligase pVHL via de-ubiquitination (Troilo et al., 2014), which promoted us to hypothesize that USP8 may be an important bridge molecule that mediates the interaction between Nrdp1 and HIF-1α. Indeed, we observed two simultaneous changes in OGD-treated neurons that support our hypothesis. First, Nrdp1 overexpression leads to increased protein ubiquitylation and suppressed interaction between Nrdp1 and USP8 (due to increased USP8 degradation). Second, USP8 directly interacts with HIF-1α, and this interaction is increased when Nrdp1 is knocked down. The interaction between USP8 and HIF-1α has been previously reported by Troilo et al. (2014). Our data suggest that under ischemic conditions, Nrdp1 upregulation may lead to an accelerated degradation of USP8, which in turn attenuates USP8’s capability to protect HIF-1α against pVHL-mediated degradation, thus interfering neuronal cells to timely adapt to hypoxic/ischemic conditions. In addition, our data also suggest that HIF-1α is an important downstream effector molecule in the pathway of Nrdp1-mediated apoptosis during ischemic neuronal injury. Future studies are warranted to explore the mechanisms underlying enhanced Nrdp1 expression under ischemic conditions.