Nr1d1, also known as REV-ERBα, belongs to the nuclear receptor (NR) family and is a heme-binding component of the circadian clock that consolidates circadian oscillators. It represses the transcription of multiple clock genes related to circadian rhythms. Moreover, it has a wide range of downstream target genes involved in autophagy, immunity, inflammation, metabolism, and aging in multiple organs, making it a key transcription factor in the gene regulatory network [1].

In multiple disease-related studies using knockout models, Nr1d1 has shown diverse functions. In abdominal aortic aneurysm (AAA), VSMC-specific Nr1d1 knockout mice inhibited AAA formation, suggesting Nr1d1 regulates AAA development by targeting the mitochondrial enzyme ACO2 [3]. In breast cancer, deletion of Nr1d1 in MMTV-PyMT transgenic mice increased tumor growth and lung metastasis, indicating its role in enhancing antitumor CD8+ T-cell responses [2]. In lung cancer, Nr1d1 deficiency in the tumor microenvironment promoted lung tumor development by activating the NLRP3 inflammasome [4]. In ulcerative colitis, intestinal-specific Nr1d1 knockout mice had disrupted immune homeostasis and declined mitophagy in intestinal epithelial cells [5]. In mouse heart-derived Sca-1+CD31-cells, overexpression of Nr1d1 in young cells inhibited proliferation and promoted apoptosis, while depletion in aged cells had the opposite effects [6].

In conclusion, Nr1d1 plays essential roles in various biological processes, especially in relation to disease development. Studies using Nr1d1 knockout or conditional knockout mouse models have revealed its significance in diseases such as AAA, breast cancer, lung cancer, ulcerative colitis, and age-related heart cell senescence, providing potential therapeutic targets for these conditions.

References:

1. Zhang-Sun, Zi-Yin, Xu, Xue-Zeng, Escames, Germaine, Acuña-Castroviejo, Darío, Yang, Yang. 2023. Targeting NR1D1 in organ injury: challenges and prospects. In Military Medical Research, 10, 62. doi:10.1186/s40779-023-00495-3. https://pubmed.ncbi.nlm.nih.gov/38072952/

2. Ka, Na-Lee, Park, Mi Kyung, Kim, Seung-Su, Lee, Ho, Lee, Mi-Ock. . NR1D1 Stimulates Antitumor Immune Responses in Breast Cancer by Activating cGAS-STING Signaling. In Cancer research, 83, 3045-3058. doi:10.1158/0008-5472.CAN-23-0329. https://pubmed.ncbi.nlm.nih.gov/37395684/

3. Sun, Ling-Yue, Lyu, Yu-Yan, Zhang, Heng-Yuan, Qian, Kun, Pu, Jun. 2022. Nuclear Receptor NR1D1 Regulates Abdominal Aortic Aneurysm Development by Targeting the Mitochondrial Tricarboxylic Acid Cycle Enzyme Aconitase-2. In Circulation, 146, 1591-1609. doi:10.1161/CIRCULATIONAHA.121.057623. https://pubmed.ncbi.nlm.nih.gov/35880522/

4. Kim, Sun Mi, Jeon, Yoon, Jang, Ji Yun, Lee, Ho. 2023. NR1D1 deficiency in the tumor microenvironment promotes lung tumor development by activating the NLRP3 inflammasome. In Cell death discovery, 9, 278. doi:10.1038/s41420-023-01554-3. https://pubmed.ncbi.nlm.nih.gov/37524704/

5. Chen, Yidong, Li, Junrong, Li, Shuang, Li, Jiamin, Zhu, Liangru. 2023. Uncovering the Novel Role of NR1D1 in Regulating BNIP3-Mediated Mitophagy in Ulcerative Colitis. In International journal of molecular sciences, 24, . doi:10.3390/ijms241814222. https://pubmed.ncbi.nlm.nih.gov/37762536/

6. Pu, Shiming, Wang, Qian, Liu, Qin, Zhou, Zuping, Wu, Qiong. 2022. Nr1d1 Mediated Cell Senescence in Mouse Heart-Derived Sca-1+CD31- Cells. In International journal of molecular sciences, 23, . doi:10.3390/ijms232012455. https://pubmed.ncbi.nlm.nih.gov/36293311/