Enolase-phosphatase 1 (ENOPH1), a member of the HAD-like hydrolase superfamily, is an enzyme involved in L-methionine and polyamine biosynthesis [1,7,8]. It has been associated with stress responses, cell proliferation, and is linked to various physiological conditions such as neurological disorders [2,6,8]. It is also involved in critical pathways like PI3K/AKT/mTOR, NF-κB, and interacts with proteins in AMPK and Hippo pathways, indicating its importance in cell regulation [1,2,3]. Genetic models, like knockout mice, have been valuable in studying its function.

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 it promotes glioma progression by activating the PI3K/AKT/mTOR signaling pathway [1]. In breast cancer, knockdown of ENOPH1 in cell lines reversed the acceleration of cell proliferation, migration, and invasion caused by its overexpression, and its oncogenic properties were restrained when the NF-κB signaling pathway was inhibited, indicating it promotes breast cancer progression mainly through activating the NF-κB pathway [3]. In hepatocellular carcinoma (HCC), ENOPH1 overexpression promoted cell migration and invasion, while downregulation inhibited these processes, and an AKT inhibitor could rescue its malignant-promoting capacity, showing it promotes HCC progression [4]. In ischemic stroke-related studies, ENOPH1 knockout mice had ameliorated cerebral ischemic injury, decreased blood-brain barrier (BBB) permeability, and inhibited extracellular matrix destruction. Mechanistically, ENOPH1 silencing enhanced the interaction between ADI1 and MT1-MMP, and regulated the ubiquitination of FKBP5 and Claudin-11, affecting neuroinflammatory stress and barrier function [5,6].

In conclusion, ENOPH1 plays a significant role in promoting the progression of several cancers, including glioma, breast cancer, and HCC, mainly by activating relevant signaling pathways. In ischemic stroke, it exacerbates early cerebral ischemia injury and BBB breakdown. The use of ENOPH1 knockout mouse models has been crucial in revealing its functions in these disease conditions, providing potential therapeutic targets for these diseases [1,3,4,5,6].