NR1D1 in tumorigenesis: dual roles, mechanisms, and therapeutic targeting.

Nuclear receptor subfamily 1, group D, member 1 (NR1D1, also known as REV-ERBα), a core circadian regulator, plays context-dependent dual roles in cancer, acting as either a tumor suppressor or oncogene. This review synthesizes current evidence on NR1D1's regulation of key oncogenic pathways: DNA repair, immunomodulation (e.g., the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, NOD-like receptor family pyrin domain containing 3(NLRP3)), metabolism, and signaling cascades such as PI3K/AKT, JAK/STAT. We highlight its clinical utility as a prognostic biomarker and therapeutic target, focusing on pharmacological modulators with demonstrated preclinical efficacy. We also critically discuss challenges in targeting NR1D1 and its potential in combination therapies, offering new insights for cancer treatment.