EPN3, an endocytic adapter protein involved in clathrin-mediated endocytosis, has diverse functions in biological processes. It is associated with multiple signaling pathways, such as JAK1/2-STAT3, NF-κB, and Wnt pathways, and plays a role in maintaining epithelial-mesenchymal transition (EMT), cell proliferation, apoptosis, and viral replication [1,2,4,5,6]. Genetic models, like gene-knockout (KO) or conditional-knockout (CKO) mouse models, could potentially help in further elucidating its functions in vivo.

In hepatitis B virus (HBV) infection, EPN3 negatively regulates HBV RNA expression, acting downstream of IFN-α and p53 [1]. In non-small cell lung cancer (NSCLC), loss-of-function experiments show that knockdown of EPN3 weakens cell proliferation, migration, and invasion, and induces apoptosis, inactivating the JAK1/2-STAT3 pathway [2]. Similar effects are seen in lung adenocarcinoma cells, where EPN3 knockdown inhibits the EMT process, reducing metastatic and invasive abilities [3]. In breast cancer, knocking down EPN3 in ER-positive cells decreases cell proliferation and increases apoptosis by regulating the NF-κB signaling pathway [4]. In glioma cells, over-expression of EPN3 promotes migration and invasion through inducing EMT, while its knockdown would likely have the opposite effect [6]. In NSCLC, EPN3 also promotes cancer progression by modulating EGFR stability [7].

In conclusion, EPN3 is involved in various biological functions including viral regulation and cancer-related processes. Studies using KO/CKO mouse models, though not directly presented in the references, could potentially further clarify its role in these diseases, providing more insights into its functions and potential as a therapeutic target in HBV-related diseases and multiple types of cancer.

References:

1. Li, Xueqian, Wang, Zhe, Zhou, Weiping, Wakae, Kousho, Liu, Guangyan. 2022. Interferon-alpha responsible EPN3 regulates hepatitis B virus replication. In Frontiers in medicine, 9, 944489. doi:10.3389/fmed.2022.944489. https://pubmed.ncbi.nlm.nih.gov/35935763/

2. Meng, Jiguang, Zhang, Chunyang, Zhu, Nengyang, Han, Zhihai, Li, Yongqun. 2023. EPN3 plays oncogenic role in non-small cell lung cancer by activating the JAK1/2-STAT3 pathway. In Environmental toxicology, 38, 1968-1979. doi:10.1002/tox.23822. https://pubmed.ncbi.nlm.nih.gov/37186036/

3. Li, Yunhe, Zhang, Pei, Tang, Guoxu, Wang, Zhenghong, Zhu, Bing. 2024. Lowering expression of Epsin-3 inhibits migration and invasion of lung adenocarcinoma cells by inhibiting the epithelial-mesenchymal transition. In Scientific reports, 14, 17069. doi:10.1038/s41598-024-68193-1. https://pubmed.ncbi.nlm.nih.gov/39048677/

4. Wu, Qianxue, Li, Qing, Zhu, Wenming, Zhang, Xiang, Li, Hongyuan. 2021. Epsin 3 potentiates the NF‑κB signaling pathway to regulate apoptosis in breast cancer. In Molecular medicine reports, 25, . doi:10.3892/mmr.2021.12531. https://pubmed.ncbi.nlm.nih.gov/34779498/

5. Schiano Lomoriello, Irene, Giangreco, Giovanni, Iavarone, Claudia, Sigismund, Sara, Di Fiore, Pier Paolo. 2020. A self-sustaining endocytic-based loop promotes breast cancer plasticity leading to aggressiveness and pro-metastatic behavior. In Nature communications, 11, 3020. doi:10.1038/s41467-020-16836-y. https://pubmed.ncbi.nlm.nih.gov/32541686/

6. Wang, Yaru, Song, Wen, Kan, Pengcheng, Yao, Xiuhua, Zhang, Biao. 2018. Overexpression of Epsin 3 enhances migration and invasion of glioma cells by inducing epithelial‑mesenchymal transition. In Oncology reports, 40, 3049-3059. doi:10.3892/or.2018.6691. https://pubmed.ncbi.nlm.nih.gov/30226603/

7. Su, Huiling, Shen, Jie, Gao, Chenzi, Dou, Jie, Guo, Min. 2025. Epsin3 promotes non-small cell lung cancer progression via modulating EGFR stability. In Cell & bioscience, 15, 14. doi:10.1186/s13578-025-01358-1. https://pubmed.ncbi.nlm.nih.gov/39910656/