RGS3 is a GTPase-activating protein that negatively regulates heterotrimeric G-protein signaling by enhancing GTP hydrolysis of Gα subunits, driving them to their inactive GDP-bound state 1. Beyond its canonical role in G-protein-coupled receptor signaling, RGS3 unexpectedly enhances GTPase activity of both mutant and wild-type KRAS proteins, explaining the sensitivity of KRASG12C-mutant lung cancers to selective inhibitors that target the GDP-bound state 2. In cardiac tissue, RGS3 and RGS4 are expressed and upregulated during hypertrophy, suggesting roles in regulating muscarinic and adrenergic signaling in myocardium 3. RGS3 exists as multiple isoforms generated from alternative promoters and exon usage, including a PDZ-domain-containing variant 4. Clinically, RGS3 upregulation in p53-mutated breast cancers correlates with reduced docetaxel responsiveness, and RGS3 knockdown enhances docetaxel-induced apoptosis 5. Recent evidence links RGS3 dysregulation to Takotsubo cardiomyopathy, where exosomal miR-126-3p from endothelial cells suppresses RGS3 expression in cardiomyocytes, causing ion channel dysfunction 6. Rare RGS3 mutations have been identified in treatment-resistant schizophrenia, suggesting roles in psychiatric disease 7.