In this report, we determined the role of connexins in GBM prognosis and TMZ resistance, explored how Cx43 activates phosphatidylinositol-3 kinase (PI3K) independent of Cx43 channels and induces TMZ resistance, and examined a candidate triple combinational therapy entailing the Cx43 inhibitor αCT1, PI3K-selective inhibitors, and TMZ in preclinical studies for its effectiveness in overcoming TMZ resistance. This evidence concerns the gene GJA1 and glioblastoma.