NFAT5, also known as tonicity-responsive enhancer-binding protein, is a member of the Rel family. It was initially recognized for regulating osmoprotective-related gene expression in renal medullary cells during osmotic response. It is sensitive to both osmolarity changes and non-hypertonic stress signals like heat shock, infection, etc. NFAT5-mediated signaling pathways are crucial in maintaining cellular homeostasis and are involved in various biological processes [2,4].

In glioblastoma, lysine methylation at K668 of NFAT5 promotes its activation. This leads to upregulation of MGMT, a transcriptional target, which is responsible for an unfavorable response to temozolomide (TMZ) therapy. Inhibition of NFAT5 K668 methylation improved TMZ efficacy in orthotopic xenografts and patient-derived xenografts (PDX) models [1].

In neuropathic pain, NFAT5 in astrocytes of the spinal dorsal horn selectively induces astrocyte swelling by regulating the expression of aquaporin-4 (AQP4). Inhibition of NFAT5-dependent astrocyte swelling alleviates neuropathic pain [3].

In pancreatic cancer, NFAT5 governs cellular plasticity-driven resistance to KRAS-targeted therapy. TGFβ induces a protein complex with NFAT5, triggering epithelial-to-mesenchymal transition (EMT) and resistance. Inhibiting NFAT5 attenuates pancreatitis-induced resistance to KRAS inhibition and extends mouse survival [5].

In summary, NFAT5 is essential for maintaining cellular homeostasis in response to osmotic and non-osmotic stress. Model-based research, especially through gene-targeting in mouse models (such as inhibiting specific methylation sites or gene deletion in relevant cell types), has revealed its significant roles in diseases like glioblastoma, neuropathic pain, and pancreatic cancer. These findings provide potential therapeutic targets for these diseases.

References:

1. Li, Yatian, Gao, Zhenyue, Wang, Yuhong, Li, Min, Ren, Yu. 2023. Lysine methylation promotes NFAT5 activation and determines temozolomide efficacy in glioblastoma. In Nature communications, 14, 4062. doi:10.1038/s41467-023-39845-z. https://pubmed.ncbi.nlm.nih.gov/37429858/

2. Yang, Xing-Liang, Wang, Xin, Peng, Bi-Wen. 2018. NFAT5 Has a Job in the Brain. In Developmental neuroscience, 40, 289-300. doi:10.1159/000493789. https://pubmed.ncbi.nlm.nih.gov/30391952/

3. He, Liqiong, Ma, Shengyun, Ding, Zijin, Guo, Qulian, Huang, Changsheng. 2024. Inhibition of NFAT5-Dependent Astrocyte Swelling Alleviates Neuropathic Pain. In Advanced science (Weinheim, Baden-Wurttemberg, Germany), 11, e2302916. doi:10.1002/advs.202302916. https://pubmed.ncbi.nlm.nih.gov/38195869/

4. Zhao, Guangze, Aghakeshmiri, Sana, Chen, Yankuan T, Yip, Fione, Yang, Decheng. 2021. NFAT5-Mediated Signalling Pathways in Viral Infection and Cardiovascular Dysfunction. In International journal of molecular sciences, 22, . doi:10.3390/ijms22094872. https://pubmed.ncbi.nlm.nih.gov/34064510/

5. Deng, Daiyong, Begum, Habeebunnisa, Liu, Tong, Soteropoulos, Patricia, Hou, Pingping. 2024. NFAT5 governs cellular plasticity-driven resistance to KRAS-targeted therapy in pancreatic cancer. In The Journal of experimental medicine, 221, . doi:10.1084/jem.20240766. https://pubmed.ncbi.nlm.nih.gov/39432061/