Nfatc4, Nuclear factor of activated T-cells, cytoplasmic 4, is a transcription factor of the NFAT family. It is activated by Ca2+/calcineurin signaling and has a crucial role in multiple biological processes. It has been implicated in various signaling pathways and is of great biological importance in processes such as cell differentiation and disease development [1]. Genetic models, like gene knockout mouse models, are valuable tools for studying its function.

In non-alcoholic steatohepatitis (NASH), NFATc4 translocates from the cytoplasm to the nucleus in hepatocytes of humans and rodents. NFATc4 knockdown in mice leads to decreased hepatic steatosis, inflammation, and fibrosis during NASH progression. Mechanistically, activated NFATc4 binds to PPARα in the nucleus, negatively regulating its transcriptional activity, and increasing lipid deposition. Also, NFATc4 activation increases OPN production and secretion from hepatocytes, enhancing macrophage-mediated inflammation and hepatic stellate cell-mediated fibrosis [2]. In optic nerve injury, NFATc4 knockout in mice increases retinal ganglion cell survival, improves retina function, and delays axonal degeneration by suppressing pro-apoptotic signaling [3]. In ovarian cancer, inhibition of the NFATC4 pathway increases chemotherapy response, while induction of NFATC4 activity results in decreased proliferation, G0 cell cycle arrest, and chemotherapy resistance both in vitro and in vivo [4].

In summary, NFATc4 is involved in multiple pathophysiological processes. Through gene knockout mouse models, its role in diseases like NASH, optic nerve injury, and ovarian cancer has been revealed. These studies highlight the potential of NFATc4 as a therapeutic target in these disease areas.

References:

1. Zhong, Qiu-Hua, Zha, Si-Wei, Lau, Andy T Y, Xu, Yan-Ming. 2022. Recent knowledge of NFATc4 in oncogenesis and cancer prognosis. In Cancer cell international, 22, 212. doi:10.1186/s12935-022-02619-6. https://pubmed.ncbi.nlm.nih.gov/35698138/

2. Du, Meng, Wang, Xiaojing, Yuan, Lin, Huang, Dan, Huang, Kai. 2020. Targeting NFATc4 attenuates non-alcoholic steatohepatitis in mice. In Journal of hepatology, 73, 1333-1346. doi:10.1016/j.jhep.2020.07.030. https://pubmed.ncbi.nlm.nih.gov/32717288/

3. Mackiewicz, Joanna, Tomczak, Julia, Lisek, Malwina, Guo, Feng, Boczek, Tomasz. 2024. NFATc4 Knockout Promotes Neuroprotection and Retinal Ganglion Cell Regeneration After Optic Nerve Injury. In Molecular neurobiology, 61, 9383-9401. doi:10.1007/s12035-024-04129-0. https://pubmed.ncbi.nlm.nih.gov/38639863/

4. Cole, Alexander J, Iyengar, Mangala, Panesso-Gómez, Santiago, Bai, Shoumei, Buckanovich, Ronald J. 2020. NFATC4 promotes quiescence and chemotherapy resistance in ovarian cancer. In JCI insight, 5, . doi:10.1172/jci.insight.131486. https://pubmed.ncbi.nlm.nih.gov/32182216/