Collectively, these results highlight the significance of targeting both the Trx and GSH systems to bypass the antioxidant role of wtp53-TrxR1 axis, induce lethal levels of ROS in both GBM cell lines and GSCs and open new avenues for the potential to repurpose Au in combination with a GSH-targeting strategy in GBM. Here, TXNRD1 is linked to glioblastoma.