RGS20 (regulator of G protein signaling 20) is a GTPase-activating protein that negatively regulates G protein-coupled receptor signaling by accelerating the GTPase activity of specific G protein alpha subunits, particularly Gα(z) and Gα(i2), driving them into their inactive GDP-bound state 1. The gene spans approximately 107 kb with at least seven exons and produces multiple splice variants, including RGSZ1 and Ret RGS, which show tissue-specific expression patterns 1. RGS20 forms functional complexes with receptors like the melatonin MT₁ receptor, where it demonstrates asymmetric coupling within receptor dimers, with one RGS20 protein binding to separate protomers of receptor dimers 2. In cancer contexts, RGS20 exhibits complex roles: it acts as an oncogene in triple-negative breast cancer, where high expression correlates with lymph node metastasis, poor clinical outcomes, and shorter relapse-free survival 3. Conversely, in gliomas, RGS20 functions as a tumor suppressor by intrinsically inhibiting WNT/β-catenin signaling, thereby reducing glioma stemness and temozolomide resistance 4. RGS20 expression is also regulated by transcription factors like SP1 through super-enhancer mechanisms in lung adenocarcinoma 5 and serves as a component of prognostic signatures for lung cancer risk stratification 67.