NFAT5 is a transcription factor that functions as a master regulator of cellular responses to osmotic stress and inflammatory signals. Primarily, NFAT5 mediates transcriptional responses to hypertonicity by binding specific DNA consensus sequences 12 and regulates expression of osmoprotective genes. Beyond osmotic regulation, NFAT5 plays diverse pathophysiological roles. In the central nervous system, NFAT5 controls astrocyte swelling through regulation of aquaporin-4 expression via the AURKB-NFAT5-AQP4 pathway, with implications for neuropathic pain management 3. NFAT5 also modulates immune responses: high-salt conditions activate NFAT5 via p38/MAPK signaling to promote pathogenic TH17 cell differentiation, contributing to autoimmune disease severity 4. In CD8+ T cells, NFAT5 promotes tumor-specific exhaustion in response to hyperosmolar tumor microenvironments, reducing anti-tumor immunity 5. Additionally, NFAT5 coordinates with HIF1A to enhance macrophage antibacterial autophagy under high-sodium conditions 6. In disease contexts, NFAT5 participates in dry eye disease pathogenesis through IL-20 upregulation 7, cerebral amyloid angiopathy via dysregulated calcineurin-NFAT signaling 8, and glioblastoma drug resistance through lysine methylation-dependent MGMT upregulation 9. These findings establish NFAT5 as a critical hub integrating osmotic, inflammatory, and pathogenic signals across multiple tissues.