Importantly, in this study, we found that NEDD4-1 was significantly upregulated in GBM, and that the transcriptional activation of endogenous NEDD4-1 degraded PTEN expression and enabled the NRF2/HO-1 antioxidant signaling response, which in turn conferred GBM cells with resistance to temozolomide (TMZ) chemotherapy. Here, PTEN is linked to glioblastoma.