NCOA1 (nuclear receptor coactivator 1) is a ligand-dependent transcriptional coactivator that directly binds nuclear receptors and stimulates their transcriptional activity 1. It functions as a critical mediator of hormone-responsive gene expression, interacting with steroid receptors (progesterone, glucocorticoid, estrogen), retinoid receptors, thyroid hormone receptors, and peroxisome proliferator-activated receptors 2. NCOA1 operates through multiple mechanisms: it possesses histone acetyltransferase activity and participates in chr2 remodeling complexes while recruiting general transcription factors 1. Beyond classical nuclear receptor signaling, NCOA1 mediates transcription factor activity for STAT family members, exemplified by its role in STAT1-mediated MMP12 transcription in pancreatic cancer-associated macrophages, where blocking this axis attenuates perineural invasion 3. Clinically, NCOA1 alterations appear in several malignancies. Gene fusions involving NCOA1/NCOA2 represent emerging biomarkers in rhabdomyosarcoma 4, while MEIS1::NCOA1 fusions define rare spindle cell sarcomas 5. NCOA1/2/3 rearrangements occur in approximately 87.5% of uterine tumors resembling ovarian sex cord tumors, suggesting these alterations drive tumorigenesis 6. These findings identify NCOA1-coactivator interactions as potential therapeutic targets, with stapled peptides successfully disrupting NCOA1/STAT6 complexes in proof-of-concept studies 7.