This is the first study to demonstrate that BMX, a novel iso-selective HDAC8 inhibitor, can enhance TMZ-mediated cytotoxic effect not only by downregulating the β-catenin/c-Myc/SOX2 pathway to inhibit stemness but also by upregulating WT-p53 mediated MGMT inhibition to induce apoptosis in TMZ-resistant GBM cells. This evidence concerns the gene TP53 and glioblastoma.