Nr1d1, also known as REV-ERBα, belongs to the nuclear receptor (NR) family. It is a heme-binding component of the circadian clock, repressing the transcription of multiple clock genes related to circadian rhythms. Additionally, it has numerous downstream target genes involved in autophagy, immunity, inflammation, metabolism, and aging in multiple organs [1].

In various disease models, Nr1d1 shows significant effects. In abdominal aortic aneurysm (AAA), VSMC-specific Nr1d1 knockout mice revealed that Nr1d1 deficiency inhibited AAA formation by restoring ACO2 dysregulation and mitochondrial dysfunction, suggesting an NR1D1-ACO2 axis in regulating mitochondrial metabolism in VSMCs [2]. In breast cancer, deletion of Nr1d1 in MMTV-PyMT transgenic mice led to increased tumor growth and lung metastasis, as NR1D1 promotes antitumor CD8+ T-cell responses by activating cGAS-STING signaling [3]. In the lung tumor microenvironment, Nr1d1-deficient mice had increased lung cancer development due to NLRP3 inflammasome activation, indicating NR1D1 as a tumor suppressor in this context [4]. In ulcerative colitis, intestinal-specific Nr1d1 knockout mice had disrupted immune homeostasis and declined mitophagy in intestinal epithelial cells (IECs), as NR1D1 positively regulates BNIP3-mediated mitophagy [5]. In mouse heart-derived Sca-1+CD31-cells, overexpression of Nr1d1 in young cells inhibited proliferation and promoted apoptosis, while its depletion in aged cells had the opposite effects [6].

In conclusion, Nr1d1 is a key regulator in the gene regulatory network with diverse functions in multiple biological processes. Gene knockout and conditional knockout mouse models have revealed its important roles in diseases such as AAA, breast and lung cancers, ulcerative colitis, and in cell senescence-related processes, providing potential therapeutic targets for these diseases.