RARG (retinoic acid receptor gamma) is a nuclear receptor that functions as a ligand-activated transcription factor, binding as a heterodimer with retinoid X receptor (RXR) to retinoic acid response elements (RARE) containing tandem AGGTCA sequences to regulate gene expression 1. RARG is essential for skeletal development and limb bud formation, and works in concert with RARA and RARB to maintain skeletal growth, matrix homeostasis, and growth plate function [UniProt annotation]. In the absence of ligand, RARG primarily activates transcription due to weak corepressor binding. Mechanistically, RARG exerts anti-inflammatory effects by interacting with TRAF6 to prevent its oligomerization and autoubiquitination, thereby inhibiting NF-κB signaling 1. Tumor-derived lactate suppresses RARG expression in macrophages through histone lactylation, promoting a protumoral phenotype via enhanced IL-6 and STAT3 signaling in colorectal cancer 1. Clinically, RARG dysregulation is implicated in acute myeloid leukemia (AML). RARG rearrangements create fusion proteins that are resistant to all-trans retinoic acid (ATRA) and arsenic trioxide therapy, conferring poor prognosis with 33.5% two-year overall survival 2. RARG fusions disrupt myeloid differentiation and promote hematopoietic stem cell self-renewal through BCL2 and ATF3 upregulation, with full leukemic transformation occurring upon concurrent WT1 loss 3. Pharmacogenomic testing of RARG variants (rs2229774) is recommended for childhood cancer patients receiving anthracycline chemotherapy, as RARG loss increases doxorubicin cardiotoxicity susceptibility 45.