NCOA6 is a pleiotropic 250 kDa nuclear receptor coactivator that functions as a multifunctional transcriptional regulator 1. It directly binds ligand-bound nuclear receptors through LxxLL motifs and activates transcription via two distinct activation domains (AD1 and AD2), operating across diverse nuclear receptor families including steroid, retinoid, thyroid hormone, vitamin D, and peroxisome proliferator-activated receptors 1. NCOA6 mediates transcriptional activation by recruiting chr20-remodeling complexes, particularly interacting with histone methyltransferases like KMT2D and histone deacetylase 1 to modulate chr20 structure 123. Beyond nuclear receptor signaling, NCOA6 localizes to the cytoplasm in activated myeloid cells where it regulates NLRP3 inflammasome assembly by promoting oligomerization of NLRP3 and ASC, thereby enhancing IL-1β and caspase-1 production 4. NCOA6 is essential for development; knockout mice die between 8.5-12.5 days post coitum with defects in heart, liver, brain and placenta development 1. Clinically, NCOA6 is overexpressed in breast, colon, lung, and pancreatic cancers, promoting cell proliferation and invasion 13. NCOA6 knockdown sensitizes pancreatic cancer cells to ferroptosis and gemcitabine through lipid metabolism alterations 5, while genetic ablation attenuates NLRP3-dependent diseases including gout 4.