NRIP1 (nuclear receptor interacting protein 1) is a transcriptional coregulator located on chromosome 21 that modulates both activation and repression by nuclear receptors including glucocorticoid, mineralocorticoid, and estrogen receptors 1. As a positive regulator of circadian clock genes, NRIP1 acts as a coactivator for RORA and RORC to stimulate transcription of BMAL1, CLOCK, and CRY1. NRIP1 suppresses energy expenditure by repressing nuclear receptors; its depletion in adipocytes enhances uncoupling protein 1 (UCP1) expression and thermogenesis independently of cAMP signaling, with implanted NRIP1-knockout adipocytes improving glucose tolerance and reducing adiposity in obese mice 12. In Down syndrome, NRIP1 overexpression contributes to mitochondrial dysfunction by negatively controlling PGC-1α-regulated pathways; NRIP1 knockdown restores mitochondrial function and ATP production 3. Pathologically, NRIP1 expression associates with poor prognosis in lung adenocarcinoma, where NRIP1 knockdown suppresses cell proliferation and induces apoptosis 4. NRIP1 is involved in renal development, and mutations associate with congenital anomalies of kidney and urinary tract type 3. Dysregulation of NRIP1 has been identified in acute myeloid leukemia through novel fusion genes and in chr21 lymphocytic leukemia, where expression signatures predict survival outcomes.