Enolase-phosphatase 1 (ENOPH1), a member of the HAD-like hydrolase superfamily, is an enzyme involved in L-methionine and polyamine biosynthesis [1,8,9]. It has been associated with stress responses, cell proliferation, and is linked to various physiological conditions such as neurological disorders [2,5,7]. It also activates signaling pathways like PI3K/AKT/mTOR and NF-κB [1,3]. Genetic models, especially knockout mice, have been crucial in studying its functions.

In glioma, ENOPH1 knockdown in cell lines inhibited cell proliferation and migration, and in an orthotopic glioma model, it suppressed tumor growth and prolonged survival, suggesting its role as an oncogenic driver [1]. In breast cancer, ENOPH1-silenced cell lines showed reduced proliferation, migration, and invasion, and its oncogenic properties were restrained when the NF-κB signaling pathway was inhibited [3]. In hepatocellular carcinoma, ENOPH1 down-regulation in vitro inhibited cell migration and invasion [4]. In cerebral ischemia, ENOPH1 knockout mice had ameliorated cerebral ischemic injury, decreased blood-brain barrier permeability, and inhibited extracellular matrix destruction [6]. Additionally, in ENOPH1 knockout mice after early ischemic stroke, changes in ubiquitination-modified proteins were observed, suggesting its role in regulating neuroinflammatory stress and barrier function [7].

In conclusion, ENOPH1 plays significant roles in cell proliferation, migration, and invasion across multiple cancer types like glioma, breast cancer, and hepatocellular carcinoma. In the context of cerebral ischemia, it is involved in blood-brain barrier dysfunction and neuroinflammatory stress. The use of ENOPH1 knockout mouse models has been instrumental in revealing these functions, providing potential therapeutic targets for cancer and ischemic stroke [1,3,4,6,7].

References:

1. Wang, Bo, Xu, Xin, Liu, Xi, Han, Tong, Hong, Jian. 2020. Enolase-phosphatase 1 acts as an oncogenic driver in glioma. In Journal of cellular physiology, 236, 1184-1194. doi:10.1002/jcp.29926. https://pubmed.ncbi.nlm.nih.gov/32654229/

2. Zhang, Xuezhong, Li, Ning, Chu, Tingting, Zhao, Haijun, Liu, Tonggang. 2025. Comprehensive pan-cancer analysis of ENOPH1 in human tumors. In Discover oncology, 16, 190. doi:10.1007/s12672-025-01965-x. https://pubmed.ncbi.nlm.nih.gov/39955431/

3. Bu, Yuhui, Hao, Jun, He, Jianchao, Liu, Yinfeng, Ma, Li. 2022. Tumor-promoting properties of enolase-phosphatase 1 in breast cancer via activating the NF-κB signaling pathway. In Molecular biology reports, 50, 993-1004. doi:10.1007/s11033-022-08066-w. https://pubmed.ncbi.nlm.nih.gov/36378417/

4. Zhuang, Hao, Qiang, Zhaoyan, Shao, Xiaowen, Wei, Wen, Li, Yongmei. 2019. Integration of metabolomics and expression of enolase-phosphatase 1 links to hepatocellular carcinoma progression. In Theranostics, 9, 3639-3652. doi:10.7150/thno.31693. https://pubmed.ncbi.nlm.nih.gov/31281503/

5. Iourov, Ivan Y, Zelenova, Maria A, Vorsanova, Svetlana G, Voinova, Victoria V, Yurov, Yuri B. . 4q21.2q21.3 Duplication: Molecular and Neuropsychological Aspects. In Current genomics, 19, 173-178. doi:10.2174/1389202918666170717161426. https://pubmed.ncbi.nlm.nih.gov/29606904/

6. Yang, Dexin, Su, Li, Li, Xiaofeng, Xie, Cong, Zhang, Yuan. 2023. Evidence that enolase-phosphatase 1 exacerbates early cerebral ischemia injury and blood-brain barrier breakdown by enhancing extracellular matrix destruction and inhibiting the interaction between ADI1 and MT1-MMP. In Experimental neurology, 365, 114410. doi:10.1016/j.expneurol.2023.114410. https://pubmed.ncbi.nlm.nih.gov/37075968/

7. Wu, Yike, Tang, Ping, Huang, Zhengzheng, Su, Li, Zhang, Yuan. 2025. Alteration of Ubiquitination in the Brain of ENOPH1 Knockout Mice after Early Ischemic Stroke. In Journal of proteome research, 24, 2349-2357. doi:10.1021/acs.jproteome.4c00913. https://pubmed.ncbi.nlm.nih.gov/40170525/

8. Su, Li, Yang, Ke, Li, Shun, Zhang, Yuan, Xu, Guozheng. 2018. Enolase-phosphatase 1 as a novel potential malignant glioma indicator promotes cell proliferation and migration. In Oncology reports, 40, 2233-2241. doi:10.3892/or.2018.6592. https://pubmed.ncbi.nlm.nih.gov/30066900/

9. Barth, Alexander, Bilkei-Gorzo, Andras, Drews, Eva, Wienker, Thomas F, Zimmer, Andreas. 2013. Analysis of quantitative trait loci in mice suggests a role of Enoph1 in stress reactivity. In Journal of neurochemistry, 128, 807-17. doi:10.1111/jnc.12517. https://pubmed.ncbi.nlm.nih.gov/24236849/