Meng Yao, Sun Peiyi, Ren Yixin, Li Guoqing, Liu Xiujun, Xu Chunjie, Dong Luyao, Li Hanhan, Zheng Zhonghui, You Xuefu, Yang Xinyi
Beijing Key Laboratory of Technology and Application for Anti-Infective New Drugs Research and Development/Laboratory of Pharmacology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
State Key Laboratory of Bioactive Substances and Function of Natural Medicines, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Int J Mol Sci. 2025 May 27;26(11):5127. doi: 10.3390/ijms26115127.
Azvudine (FNC) is a novel cytidine analogue that is widely used in the treatment of infectious diseases such as AIDS and COVID-19. Previous studies have demonstrated its anticancer activity in various cancer cell lines, including non-Hodgkin's lymphomas and lung adenocarcinoma cell lines. However, its effects on hepatocellular carcinoma (HCC) and the underlying mechanisms remain unclear. This study aimed to investigate the anti-epithelial-mesenchymal transition (anti-EMT) activity of FNC and evaluate its potential application in HCC treatment. We found that FNC significantly inhibits the migration of the liver cancer cell line Huh7 by downregulating key EMT markers, such as matrix metalloproteinases (MMPs) and E-cadherin, at both the transcriptional and protein expression levels. Notably, we found that FNC inhibits HEY proteins, particularly HEY1, a transcriptional regulator of the Notch signalling pathway that is overexpressed in approximately 50% of HCC patients. To identify the primary target of FNC, microscale thermophoresis (MST) and molecular dynamics (MD) simulations were performed, revealing that FNC directly binds to Jagged1. This study provides valuable insights into the therapeutic potential of FNC in HCC treatment and elucidates its underlying mechanisms.
阿兹夫定（FNC）是一种新型胞苷类似物，广泛用于治疗艾滋病和新冠肺炎等传染病。先前的研究已证明其在包括非霍奇金淋巴瘤和肺腺癌细胞系在内的多种癌细胞系中具有抗癌活性。然而，其对肝细胞癌（HCC）的影响及潜在机制仍不清楚。本研究旨在探讨FNC的抗上皮-间质转化（抗EMT）活性，并评估其在HCC治疗中的潜在应用。我们发现，FNC通过在转录和蛋白表达水平下调关键的EMT标志物，如基质金属蛋白酶（MMPs）和E-钙黏蛋白，显著抑制肝癌细胞系Huh7的迁移。值得注意的是，我们发现FNC抑制HEY蛋白，尤其是HEY1，HEY1是Notch信号通路的转录调节因子，在约50%的HCC患者中过表达。为了确定FNC的主要靶点，进行了微量热泳动（MST）和分子动力学（MD）模拟，结果显示FNC直接与Jagged1结合。本研究为FNC在HCC治疗中的治疗潜力提供了有价值的见解，并阐明了其潜在机制。
