Nfat5, also known as tonicity-responsive enhancer-binding protein, is a member of the Rel family. It was initially identified in renal medullary cells, where it regulates the expression of osmoprotective-related genes during the osmotic response. It is also sensitive to various stress signals like heat shock, infection, etc. NFAT5-mediated signaling pathways play crucial roles in maintaining cellular homeostasis and are involved in numerous biological processes [2,5]. Genetic models such as gene knockout (KO) and conditional knockout (CKO) mouse models are valuable for studying its functions.

In glioblastoma, lysine methylation of NFAT5 at K668 promotes its activation, leading to upregulation of MGMT and unfavorable response to temozolomide therapy. Inhibition of this methylation improves the efficacy of temozolomide in xenograft models [1].

In neuropathic pain, NFAT5 selectively induces astrocyte swelling in the spinal dorsal horn by regulating aquaporin-4 expression, and its inhibition alleviates neuropathic pain [3].

In the tumor microenvironment, NFAT5 promotes CD8+ T cell exhaustion in a tumor-selective manner. Deletion of NFAT5 in CD8+ T cells improves tumor control [4].

In pancreatic cancer, NFAT5 governs cellular plasticity-driven resistance to KRAS-targeted therapy. Inhibiting NFAT5 attenuates pancreatitis-induced resistance to KRAS inhibition and extends mouse survival [6].

In conclusion, NFAT5 is a key regulator in maintaining cellular homeostasis, with its functions extending to multiple disease areas. Findings from KO/CKO mouse models have revealed its significance in glioblastoma treatment response, neuropathic pain, tumor-induced T cell exhaustion, and pancreatic cancer resistance to therapy, highlighting its potential as a therapeutic target.