GPS2 (G protein pathway suppressor 2) is a multifunctional transcriptional coregulator and core component of the NCoR/SMRT co-repressor complex with diverse roles in cellular metabolism, differentiation, and cancer biology 1 2. Mechanistically, GPS2 functions through multiple pathways: it suppresses aerobic glycolysis in breast cancer by stabilizing RACK1-mediated HIF-1α degradation, thereby reducing expression of glycolytic enzymes 1; it undergoes liquid-liquid phase separation to interact with LATS1, suppressing Hippo pathway activity and promoting lipid metabolic reprogramming in colorectal cancer 3; and it inhibits K63-ubiquitination of translation factors and RNA-binding proteins to regulate mitochondria-associated protein synthesis 4. GPS2 also mediates protein-protein interactions critical for hematopoiesis, including bridging ANKRD26-ETV6 interactions in thrombocytopoiesis and promoting erythroid differentiation through NCOR1-dependent mechanisms 5 6. Additionally, GPS2 stabilizes ATF4 protein to confer l-asparaginase resistance in acute lymphoblastic leukemia 7. Disease relevance includes both tumor suppression in breast cancer and oncogenic roles in colorectal cancer and leukemia, with clinical significance for metabolic and hematologic malignancies 1 3 7.