Resveratrol as a Novel YAP Inhibitor Targeting Glioblastoma Progression and Sensitizing to Chemotherapy

Dysregulation of YAP, the terminal effector of the Hippo pathway, contributes to cancer progression and drug resistance. Its role in glioblastoma (GBM), the most aggressive brain cancer, remains incompletely understood. Single-cell RNA sequencing data from a published GBM dataset were reanalyzed to assess YAP expression across cell populations. YAP was silenced via shRNA in GBM cell lines (U-251 MG, U-87 MG) and patient-derived GBM cells. Resveratrol (RV), a natural blood-brain barrier-permeable compound, was evaluated for growth inhibition and YAP-targeted effects. Functional assays measured proliferation, spheroid formation, migration, invasion, and drug sensitivity. YAP and its cofactor TEAD were highly upregulated in GBM cells compared with normal brain and stromal cells. YAP depletion by shRNA suppressed proliferation, spheroid formation, migration, and invasion. RV treatment similarly inhibited YAP expression, reducing proliferation and viability in monolayer and 3D spheroid cultures, and impairing migration and invasion via epithelial-mesenchymal transition (EMT) inhibition. RV-mediated YAP suppression also enhanced sensitivity to temozolomide (TMZ) and carmustine (BCNU), increasing their cytotoxicity in GBM cells. RV acts as a novel YAP inhibitor in GBM, impairing malignant phenotypes and potentiating the effects of standard chemotherapy. These findings support RV as a potential adjunct in YAP-targeted GBM therapy, warranting further in vivo validation for clinical translation.