Nfatc1, also known as nuclear factor of activated T-cells 1, is a crucial transcription factor. It is essential in the immune system, cardiac valve morphogenesis, lymphatic endothelial development, osteoblast differentiation, and osteoclastogenesis. In osteoclastogenesis, it is a master regulator of RANKL-induced osteoclast differentiation and is involved in osteoclast fusion and activation through up-regulating genes related to osteoclast functions [6]. The Ca2+-triggered transcriptional activity of Nfatc1 is also important in orchestrating the osteogenesis of skeletal stem cells [5].

In non-alcoholic fatty liver disease (NAFLD), hepatocyte-specific depletion of Nfatc1 can prevent mice from disease acceleration. High-fat diet increases Nfatc1 expression, which promotes NAFLD progression through chronic ER stress sensing and activation of terminal UPR signalling in hepatocytes [1]. In osteoclast precursors, NFATc1-mediated upregulation of SLC7A11 induces sensitivity to TXNRD1 inhibitors. Inhibition of NFATc1 can rescue the cell death caused by TXNRD1 inhibitors in osteoclast precursors [2]. Artesunate, by suppressing the PLCγ1-Ca2+-NFATc1 signaling pathway, attenuates LPS-induced osteoclastogenesis [3]. Erianin, acting as an NFATc1 inhibitor, can prevent breast cancer-induced osteoclastogenesis and bone destruction [4]. Inhibition of Ca2+/NFATc1 signaling in skeletal stem cells directly impairs osteogenesis and bone regeneration [5].

In conclusion, Nfatc1 is vital in multiple biological processes, especially osteoclast-related functions and NAFLD progression. Gene knockout or conditional knockout mouse models have been instrumental in revealing its role in these processes. Understanding Nfatc1 helps in clarifying the mechanisms of related diseases and may provide potential therapeutic targets for diseases like NAFLD, bone metabolic diseases, and breast-cancer-induced bone destruction.

References:

1. Latif, Muhammad Umair, Schmidt, Geske Elisabeth, Mercan, Sercan, Bogeski, Ivan, Ellenrieder, Volker. 2022. NFATc1 signaling drives chronic ER stress responses to promote NAFLD progression. In Gut, 71, 2561-2573. doi:10.1136/gutjnl-2021-325013. https://pubmed.ncbi.nlm.nih.gov/35365570/

2. Zhong, Zeyuan, Zhang, Chongjing, Ni, Shuo, Yi, Chengqing, Yu, Baoqing. 2023. NFATc1-mediated expression of SLC7A11 drives sensitivity to TXNRD1 inhibitors in osteoclast precursors. In Redox biology, 63, 102711. doi:10.1016/j.redox.2023.102711. https://pubmed.ncbi.nlm.nih.gov/37148740/

3. Zeng, Xiang-Zhou, Zhang, Yue-Yang, Yang, Qin, Liu, Shu-Wen, Li, Xiao-Juan. 2019. Artesunate attenuates LPS-induced osteoclastogenesis by suppressing TLR4/TRAF6 and PLCγ1-Ca2+-NFATc1 signaling pathway. In Acta pharmacologica Sinica, 41, 229-236. doi:10.1038/s41401-019-0289-6. https://pubmed.ncbi.nlm.nih.gov/31431733/

4. Zheng, Jiehuang, He, Weili, Chen, Yan, Tan, Yanhui, Li, Xiaojuan. 2024. Erianin serves as an NFATc1 inhibitor to prevent breast cancer-induced osteoclastogenesis and bone destruction. In Journal of advanced research, 69, 399-411. doi:10.1016/j.jare.2024.03.021. https://pubmed.ncbi.nlm.nih.gov/38556044/

5. Yu, Fanyuan, Li, Feifei, Yu, Peng, Zhou, Bin, Ye, Ling. . Identification and characterization of NFATc1+ skeletal stem cells in bone regeneration. In Cell reports, 41, 111599. doi:10.1016/j.celrep.2022.111599. https://pubmed.ncbi.nlm.nih.gov/36351390/

6. Zhao, Qingxiao, Wang, Xi, Liu, Yuehua, He, Aimin, Jia, Ruokun. 2009. NFATc1: functions in osteoclasts. In The international journal of biochemistry & cell biology, 42, 576-9. doi:10.1016/j.biocel.2009.12.018. https://pubmed.ncbi.nlm.nih.gov/20035895/