Znrf2, Zinc and ring finger 2, is an E3 ubiquitin ligase. It plays roles in multiple biological processes such as regulating the Na+/K+ATPase [4]. It is also involved in the mTORC1-related pathways, like promoting mTORC1's amino acid-stimulated translocation to lysosomes and its activation, and being a substrate of mTORC1 itself [7].

In cancer, Znrf2 generally shows higher expression in tumors compared to normal tissues. In non-small cell lung cancer (NSCLC), high Znrf2 levels are correlated with poor prognosis, and overexpression increases cell growth while depletion decreases it [5]. In glioma, its elevated expression is related to increased grades and worse prognosis, and knockdown impairs cell proliferation and glycolysis [2]. In breast cancer, it is highly expressed, and knockdown suppresses cell proliferation and induces apoptosis [3]. In osteosarcoma, high Znrf2 levels and low miR-100 levels are observed, and Znrf2 overexpression increases cell growth [6]. In papillary thyroid cancer, lncRNA TTN-AS1 modulates the miR-153-3p/Znrf2 axis to facilitate tumorigenesis [8]. In cerebral ischemia/reperfusion injury, overexpression of Znrf2 reduces injury by inhibiting mTORC1-mediated autophagy [1].

In conclusion, Znrf2 has diverse functions in various biological processes and diseases. In cancer, it often acts as an oncogene promoting tumor growth and progression. In cerebral ischemia/reperfusion injury, it plays a protective role. Studies on Znrf2 using different models help understand its functions in disease mechanisms, providing potential targets for treatment.

References:

1. Gu, Chao, Yang, Junqing, Luo, Ying, Liu, Xia, Wang, Hong. 2021. ZNRF2 attenuates focal cerebral ischemia/reperfusion injury in rats by inhibiting mTORC1-mediated autophagy. In Experimental neurology, 342, 113759. doi:10.1016/j.expneurol.2021.113759. https://pubmed.ncbi.nlm.nih.gov/33992580/

2. Xi, Yunlan, Yang, Qingqing, Wang, Yixuan, Yu, Shizhu, Zhou, Xuexia. 2025. ZNRF2 is essential for gliomagenesis through orchestrating glycolysis and acts as a promising therapeutic target in glioma. In Journal of translational medicine, 23, 185. doi:10.1186/s12967-025-06202-1. https://pubmed.ncbi.nlm.nih.gov/39953597/

3. Liu, Jin-Tao, Sun, Zhen-Xuan, Zhong, Rui, Zhang, Lei, Chen, Bo. 2023. ZNRF2 as an oncogene is transcriptionally regulated by CREB1 in breast cancer models. In Human cell, 36, 1501-1515. doi:10.1007/s13577-023-00913-7. https://pubmed.ncbi.nlm.nih.gov/37165255/

4. Hoxhaj, Gerta, Najafov, Ayaz, Toth, Rachel, Prescott, Alan R, MacKintosh, Carol. 2012. ZNRF2 is released from membranes by growth factors and, together with ZNRF1, regulates the Na+/K+ATPase. In Journal of cell science, 125, 4662-75. doi:10.1242/jcs.110296. https://pubmed.ncbi.nlm.nih.gov/22797923/

5. Zhang, X-F, Guo, Z-Q, Zhao, C-C, Li, C, Wang, Z. . The role of ZNRF2 in the growth of non-small cell lung cancer. In European review for medical and pharmacological sciences, 20, 4011-4017. doi:. https://pubmed.ncbi.nlm.nih.gov/27775798/

6. Xiao, Qiang, Yang, Yu, An, Qing, Qi, Yong. . MicroRNA-100 suppresses human osteosarcoma cell proliferation and chemo-resistance via ZNRF2. In Oncotarget, 8, 34678-34686. doi:10.18632/oncotarget.16149. https://pubmed.ncbi.nlm.nih.gov/28416774/

7. Hoxhaj, Gerta, Caddye, Edward, Najafov, Ayaz, Prescott, Alan R, MacKintosh, Carol. 2016. The E3 ubiquitin ligase ZNRF2 is a substrate of mTORC1 and regulates its activation by amino acids. In eLife, 5, . doi:10.7554/eLife.12278. https://pubmed.ncbi.nlm.nih.gov/27244671/

8. Cui, Zhenghui, Luo, Zhiyan, Lin, Zimei, Hong, Yurong, Yan, Caoxin. 2019. Long non-coding RNA TTN-AS1 facilitates tumorigenesis of papillary thyroid cancer through modulating the miR-153-3p/ZNRF2 axis. In The journal of gene medicine, 21, e3083. doi:10.1002/jgm.3083. https://pubmed.ncbi.nlm.nih.gov/30811764/