EPN3, also known as epsin 3, is a clathrin-binding membrane protein involved in clathrin-mediated endocytosis [1,3,5,6]. It is associated with multiple cellular signaling pathways, such as the JAK1/2-STAT3, NF-κB, Notch, and WNT/β-catenin pathways, and plays important roles in various biological processes and disease conditions [2,4,6]. Genetic models, like gene knockout models, could potentially help further clarify its functions.

In terms of disease-related functions, EPN3 negatively regulates the expression of HBV RNA, acting downstream of IFN-α and p53 [1]. In non-small cell lung cancer (NSCLC), EPN3 acts as an oncogene by activating the JAK1/2-STAT3 pathway, promoting cell proliferation, migration, and invasion, and inhibiting apoptosis [2]. Lowering EPN3 expression in lung adenocarcinoma cells reduces their metastatic and invasive ability by inhibiting the epithelial-mesenchymal transition (EMT) [3]. In breast cancer, EPN3 promotes cell proliferation and inhibits apoptosis by regulating the NF-κB signaling pathway [4]. In glioma cells, overexpression of EPN3 enhances migration and invasion by inducing EMT through activation of certain transcription factors and involvement in the Notch and WNT/β-catenin signaling pathways [6]. In NSCLC, EPN3 also promotes cancer progression by modulating EGFR stability [7].

In conclusion, EPN3 is a multi-functional protein with roles in viral regulation and cancer development. Through model-based research, it has been shown to be involved in key cellular processes relevant to HBV infection and multiple cancers. Understanding EPN3's functions provides potential therapeutic targets for treating HBV-related diseases and cancers, especially NSCLC, breast cancer, and glioma.