Nfatc3, the nuclear factor of activated T cells cytoplasmic member 3, is a transcriptional regulator. It is involved in multiple cellular processes, with its activity regulated by phosphorylation and other post-translational modifications. For instance, in resting cells, heavily phosphorylated Nfatc3 is in the cytoplasm, while dephosphorylated Nfatc3 translocates to the nucleus upon stimuli like hypoxia [3].

Macrophage-specific Nfatc3 knockout mice demonstrated that Nfatc3 deficiency led to atherosclerotic plaque formation, as Nfatc3 deficiency in macrophages promoted foam cell formation by enhancing lipid uptake. Nfatc3 directly up-regulated miR-204 levels, and miR-204 reduction reversed the beneficial effects of Nfatc3 in macrophages, indicating the NFATc3/miR-204 axis as a potential anti-atherosclerosis target [1].

In bleomycin-induced pulmonary fibrosis mouse models, Nfatc3 deficiency (NFATc3+/-) was protective, and adoptive transfer of NFATc3+/+ macrophages restored susceptibility, showing that Nfatc3 promotes pulmonary inflammation and fibrosis by regulating CCL2 and CXCL2 production in macrophages [2,4].

In high-fat diet-fed Nfatc3−/− mice, insulin sensitivity and glucose tolerance were improved, with reduced M1 macrophage content and pro-inflammatory factors in visceral adipose tissue, suggesting Nfatc3's role in M1 macrophage polarization, adipose tissue inflammation, and insulin resistance [5].

In conclusion, Nfatc3 plays diverse and crucial roles in multiple disease-related biological processes. Studies using Nfatc3 knockout or conditional knockout mouse models have revealed its functions in atherosclerosis, pulmonary fibrosis, and adipose tissue inflammation. These findings provide valuable insights into the mechanisms of these diseases and potential therapeutic targets related to Nfatc3.