NCOA2 is a transcriptional coactivator that enhances the activity of steroid and nuclear receptors through interaction with their ligand-binding domains. It works with NCOA1 to regulate energy balance between white and brown adipose tissues and plays a critical role in glucose metabolism by acting as a coactivator for RORA to modulate G6PC1 expression. NCOA2 also positively regulates circadian clock function through the CLOCK-BMAL1 heterodimer and suppresses Hedgehog pathway signaling by directly inhibiting the transcription factor GLI 1. NCOA2 is implicated in multiple malignancies through recurrent gene fusions. ETV6-NCOA2 fusion initiates T/myeloid mixed-phenotype leukemia by forming a transcriptional complex with p300 that derepresses myeloid genes while activating lymphoid programs 2. VGLL2-NCOA2 fusion drives infantile rhabdomyosarcoma by leveraging developmental programs, particularly through reactivation of ARF6 3, while HEY1-NCOA2 fusion characterizes mesenchymal chondrosarcoma 4. MEF2D::NCOA2 fusion defines a distinct indolent vulvovaginal smooth muscle tumor with myxoid features 5. Additionally, NCOA2 is amplified in approximately 11% of prostate cancers 6, and ETV3::NCOA2 fusion occurs in indeterminate dendritic cell histiocytosis 7. These diverse fusion partners suggest NCOA2 functions as a versatile coactivator platform that, when dysregulated, drives multiple tumor types across tissues and age groups.