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 and has numerous downstream target genes involved in autophagy, immunity, inflammation, metabolism, and aging in multiple organs [1]. Genetic models, such as knockout (KO) and conditional knockout (CKO) mouse models, are valuable for studying its functions.

In various disease-related studies using these models: Nr1d1 knockout in vascular smooth muscle cells (VSMCs) inhibited abdominal aortic aneurysm (AAA) formation, with ACO2, a key enzyme of the mitochondrial tricarboxylic acid cycle, identified as a direct target of NR1D1 [3]. In MMTV-PyMT transgenic mice, deletion of Nr1d1 led to increased breast tumor growth and lung metastasis, and NR1D1 was found to enhance antitumor CD8+ T-cell responses via cGAS-STING pathway activation [2]. In the tumor microenvironment of a lung cancer orthotopic model, NR1D1 deficiency promoted lung tumor development by activating the NLRP3 inflammasome [4]. In intestinal-specific Nr1d1 knockout mice, disrupted immune homeostasis and declined mitophagy in intestinal epithelial cells (IECs) were observed in ulcerative colitis (UC), and NR1D1 was shown to regulate BNIP3-mediated mitophagy [5]. In aged mouse heart-derived Sca-1+CD31-cells, depletion of Nr1d1 promoted cell proliferation and inhibited apoptosis [6].

In conclusion, Nr1d1 is crucial for maintaining normal physiological functions related to circadian rhythms and a wide range of physiopathological processes. Studies using KO/CKO mouse models have revealed its role in diseases like AAA, breast cancer, lung cancer, UC, 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/