GRK5 Overexpression Drives Malignant Glioma Progression Through HDAC7 Alongside Canonical GPCR Signaling

G-protein-coupled receptor kinase 5 (GRK5) plays a pivotal role in various pathological conditions, particularly in cancer. While our previous work identified elevated GRK5 expression in gliomas, its functional significance remains unclear. Using clinical glioma specimens and U251 cell models with GRK5 knockdown or overexpression, we investigated the oncogenic functions of GRK5 through Cell Counting Kit-8, flow cytometry, transwell, and wound healing assays. Underlying mechanisms were explored via Western blot, immunofluorescence, and transcriptomic analysis. GRK5 overexpression correlated with glioma malignancy and drove tumor progression by enhancing proliferation, migration, and invasion while suppressing apoptosis through Bax downregulation. This oncogenic activity partially involved β-arrestin-mediated desensitization of the G-protein-coupled receptor pathway. Crucially, GRK5 facilitated the translocation of HDAC7 from the nucleus to the cytoplasm. Cytosolic HDAC7 subsequently deacetylated cortactin, which in turn stabilized F-actin and enhanced the MSN/CD44 complex expression and stability, thereby driving the MES transition-a hallmark of aggressive glioblastoma. Inhibition of HDAC7 abolished the GRK5-induced upregulation of MSN and CD44. We unveil MSN as a non-canonical GRK5/HDAC7 axis that promotes glioma malignancy by modulating the cortactin/MSN/CD44 pathway. Targeting this axis potentially represents a promising therapeutic strategy against gliomas.