NR1D2 is a nuclear receptor that functions as a transcriptional repressor coordinating circadian rhythm and metabolic homeostasis in a heme-dependent manner 1. As a core circadian clock component, NR1D2 directly represses expression of clock genes BMAL1 and CLOCK by binding DNA as monomers or homodimers to specific response elements (RevRE or RevDR-2) 2. Heme binding stimulates NR1D2 interaction with the NCOR1/HDAC3 corepressor complex, enhancing transcriptional repression 1. Beyond circadian regulation, NR1D2 controls lipid metabolism and energy homeostasis in skeletal muscle and liver, repressing genes involved in fatty acid oxidation and lipid synthesis 3. NR1D2 also negatively regulates inflammatory responses and can act as a transcriptional activator of metabolic genes including SREBF1 3. Dysregulation of NR1D2 contributes to multiple pathologies. NR1D2 downregulation in lacrimal glands impairs lipid metabolism and mitochondrial function, contributing to post-surgical dry eye disease; SR9011 activation restores function 3. Conversely, NR1D2 overexpression in glioblastoma promotes cell proliferation and motility through AXL-mediated PI3K/AKT signaling 4. In castration-resistant prostate cancer, NR1D2 overexpression in small cell carcinoma drives lineage plasticity 5, while NR1D2 integrates Hippo and Notch pathways promoting tumor malignancy when steroid hormone signaling is inhibited 6. Pharmacological REV-ERB agonists (SR9009/SR9011) selectively induce apoptosis in cancer cells by regulating autophagy and lipogenesis 7, offering therapeutic potential for circadian-based cancer treatment.