NCOA5 is a nuclear receptor coactivator that functions as a dual-function coregulator of steroid receptors (ESR1/ESR2) and the orphan receptor NR1D2, operating independently of the AF-2 domain [UniProt]. It enhances estrogen receptor α-modulated transcriptional activity while suppressing MYC expression in response to 17-beta-estradiol [UniProt]. Mechanistically, NCOA5 regulates multiple cellular pathways including the Notch3 signaling pathway in cervical cancer 1, the NRF2-mediated transactivation of PRDX6 in lung cancer 2, and epithelial-to-mesenchymal transition (EMT) in hepatocellular carcinoma 3. In male reproduction, NCOA5 regulates epididymal sperm maturation through suppression of IL-6 expression 4. Clinically, NCOA5 acts as a tumor suppressor in multiple cancers. Low NCOA5 expression predicts poor prognosis in cervical cancer and correlates with increased stage and histological grade 1, while high expression associates with worse prognosis in epithelial ovarian cancer 5. In non-small cell lung cancer, low NCOA5 expression correlates with lymph node metastasis and poor prognosis, and NCOA5 overexpression reverses cisplatin resistance by suppressing the PRDX6/ROS axis 2. Additionally, NCOA5 polymorphisms confer susceptibility to autoimmune diseases including psoriasis 6 and multiple sclerosis 7, suggesting its broader immunoregulatory function.