USP8 is a substrate of Nrdp1, and interestingly, it is also a de-ubiquitination enzyme (Wu et al., 2004; De Ceuninck et al., 2013). This de-ubiquitination activity has made USP8 a stabilizing molecule for HIF-1α protein, in which USP8 prevents HIF-1α from pVHL-mediated degradation (Troilo et al., 2014). It is well known that HIF-1α plays a vital role in attenuating brain tissue damage through promoting adaptive response during ischemic stroke (Helton et al., 2005; Baranova et al., 2007; Fan et al., 2009; Singh et al., 2012; Zhang et al., 2014; Yang Y. et al., 2017). These data raise an important hypothesis that ischemia-induced Nrdp1 upregulation may contribute to ischemic neuronal injury via downregulating USP8 (via degradation) and thus destabilizing HIF-1α in ischemic neurons.