{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNFAT5, also known as tonicity‐responsive enhancer‐binding protein (TonEBP), is a versatile transcription factor central to cellular adaptation under stress. It is activated by hypertonic and hypoxic cues through a complex network of kinase‐ and phosphatase‐mediated events that regulate its phosphorylation, nuclear trafficking, and DNA binding. Multiple studies have highlighted that NFAT5 activation involves signaling via p38 MAP kinase and Fyn, ATM‐dependent phosphorylation, c‐Abl and CDK5 modifications, and even PLC-γ1 interactions. These post‐translational modifications, along with regulatory inputs from nuclear export factors (such as CRM1 and CK1) and inhibition by phosphatases (including MKP‑1 and SHP‑1), control its subcellular localization and transactivating activity. Moreover, structural analyses reveal that NFAT5 uniquely encircles its DNA target, while recent evidence also implicates its role in resolving R-loop structures under DNA damage and in response to hypoxia, thereby safeguarding genomic integrity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer, NFAT5 acts as a pro‐tumorigenic factor that drives invasive and migratory behaviors. Elevated NFAT5 expression has been associated with the invasive phenotype in breast carcinomas, and its aberrant activity underlies metabolic reprogramming and proliferation in pancreatic ductal adenocarcinoma, lung adenocarcinoma, and hepatitis B virus–associated hepatocellular carcinoma. Furthermore, studies indicate that cofactors such as RNA helicases can fine-tune NFAT5 by modulating both its transcriptional coactivator function and its alternative splicing, thereby intricately controlling tumor cell migration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNFAT5 is also pivotal in regulating immune responses and inflammation. It collaborates with NF-κB signaling pathways to enhance the expression of proinflammatory genes in response to hypertonic challenges, thereby influencing T-cell homeostasis, macrophage activation, and the functional differentiation of regulatory T cells. In autoimmune diseases such as rheumatoid arthritis and thymoma-associated myasthenia gravis, NFAT5 modulates cytokine production and cell survival. Additionally, during infections like tuberculosis and HIV, NFAT5 is directly exploited to stimulate viral enhancer activity, which in turn facilitates viral replication within host immune cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in stress adaptation and immunity, NFAT5 is essential for proper tissue differentiation and homeostasis. It regulates chondrogenic differentiation of progenitor cells, modulates aquaporin-2 expression in intervertebral disc cells, and attenuates Wnt/β-catenin signaling to promote intestinal epithelial differentiation. In vascular smooth muscle and endothelial cells, NFAT5 responds to biomechanical stretch and high-salt conditions, contributing to vascular remodeling, inflammasome activation, and the pathogenesis of diabetic nephropathy and peritoneal fibrosis. Its activity in these diverse tissues is further refined by alternative splicing events and lipid modifications that affect its subcellular distribution and functional output."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "35", "end_ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Valerie Horsley, Grace K Pavlath "}, {"type": "b", "children": [{"type": "t", "text": "NFAT: ubiquitous regulator of cell differentiation and adaptation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.200111073"}], "href": "https://doi.org/10.1083/jcb.200111073"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11877454"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11877454"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "J Trama, Q Lu, R G Hawley, et al. 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