The fact that Nrdp1’s substrate USP8 can protect HIF-1α from pVHL-mediated degradation (Troilo et al., 2014) led us to hypothesize that Nrdp1 may act on USP8 to regulate HIF-1α expression under OGD condition. To test this, we investigated the change of USP8 in OGD-treated neurons and the impact of Ad-Nrdp1 and Ad-si-Nrdp1 on USP8 expression. As shown in Figures 4A,B, 6-h OGD induced a significant decrease in the level of USP8 proteins in the cells transfected with Ad-si-control. Importantly, this reduction was partially reversed when Nrdp1 was knocked down by Ad-si-Nrdp1, and was exacerbated when Nrdp1 was overexpressed by Ad-Nrdp1 (Figures 4C,D). Collectively, these results suggest that Nrdp1 may contribute to OGD-induced neuronal cell death via suppressing HIF-1α and USP8 expression.