RGS20 reduces glioma stemness and temozolomide resistance by intrinsically inhibiting the WNT/β-catenin signaling pathway

G protein-coupled receptors (GPCRs) play a pivotal role in maintaining the stemness of both normal and cancer stem cells. However, the function of the regulator of G protein signaling (RGS) family, particularly in tumor stem cells, remains poorly understood. Through bioinformatics analysis of clinical data, we identified RGS20 as a potential regulator of glioma stemness and temozolomide (TMZ) resistance, which may significantly influence patient prognosis. Subsequent in vitro and in vivo experiments demonstrated that RGS20 inhibition markedly enhanced tumor sphere formation and upregulated stem cell markers by intrinsically activating the WNT/β-catenin signaling pathway in a ligand-independent manner, thereby promoting tumorigenesis and ultimately leading to TMZ resistance. Furthermore, in human glioblastoma specimens, β-catenin signaling associated with low RGS20 expression was significantly enriched in hypoxic regions, suggesting that this mechanism may support the maintenance of glioma stem cells (GSCs) and drive TMZ resistance within the hypoxic niche. Our findings reveal a novel intracellular molecular mechanism—RGS20/β-catenin—that promotes glioma progression by mimicking environmental cues. Targeting this mechanism could provide new therapeutic strategies for glioma treatment.