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 plays significant roles in multiple biological processes. It has been implicated in the regulation of T-cell differentiation and is involved in various pathophysiological processes [1,2].

In non-alcoholic steatohepatitis (NASH), Nfatc4 translocates from the cytoplasm to the nucleus in hepatocytes of both humans and rodents. Nfatc4 knockdown in mice resulted in decreased hepatic steatosis, inflammation, and fibrosis during NASH progression. Mechanistically, activated Nfatc4 binds to PPARα in the nucleus and negatively regulates its transcriptional activity, impairing fatty acid oxidation and increasing lipid deposition. Also, Nfatc4 activation increases OPN production and secretion from hepatocytes, enhancing macrophage-mediated inflammation and hepatic stellate cell-mediated fibrosis via paracrine signaling [2].

In ovarian cancer, induction of Nfatc4 activity led to decreased proliferation, G0 cell cycle arrest, and chemotherapy resistance in vitro and in vivo. Nfatc4-driven quiescence was in part via downregulation of MYC [4].

In cutaneous squamous cell carcinoma (CSCC), overexpression of Nfatc4 in mouse models suppressed cell proliferation and invasion, and promoted apoptosis, suggesting it might be a tumour suppressor gene [5].

In optic nerve injury, NFATc4 knockout in mice increased retinal ganglion cell (RGC) survival, improved retina function, and delayed axonal degeneration by suppressing pro-apoptotic signaling [3].

In summary, Nfatc4 has diverse functions in different biological processes and disease conditions. The use of gene knockout mouse models has been crucial in revealing its role in diseases such as NASH, ovarian cancer, CSCC, and optic nerve injury, providing potential therapeutic targets for these conditions.