NFAT5 is an osmosensitive transcription factor that regulates osmoprotective and inflammatory gene expression in response to hypertonicity. It binds specific DNA consensus sequences and mediates transcriptional responses to changes in cellular osmolarity, positively regulating genes such as LCN2 and S100A4. Beyond osmotic stress, NFAT5 participates in DNA damage responses by preventing R-loop formation and is implicated in diverse pathological processes. In autoimmune contexts, high salt concentrations activate NFAT5 through the p38/MAPK pathway to promote pathogenic TH17 cell differentiation 1, linking dietary salt intake to autoimmune disease risk. In pancreatic cancer, NFAT5 forms a complex with SMAD proteins downstream of TGFβ signaling to drive epithelial-to-mesenchymal transition and resistance to KRAS-targeted therapy 2. NFAT5 also regulates astrocyte swelling via aquaporin-4 expression in neuropathic pain 3 and suppresses CVB3 replication in cardiac tissue through type I interferon signaling 4. Recent studies propose that NFAT5 dysregulation in pericytes contributes to cerebral amyloid angiopathy in APOE4 carriers 5, while calcineurin-NFAT5 inhibition and targeting NFAT5-dependent pathways represent emerging therapeutic strategies across multiple disease contexts.