Wang Le, Song Hongxiao, Xu Fengchao, Zhu Yujia, Huang Mian, Xu Jing, Li Xiaolu, Wang Fei, Yang Fan, Lei Yang, Gao Pujun, Tan Guangyun
Department of Hepatology, Center of Infectious Diseases and Pathogen Biology, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun, Jilin, China.
Jilin Provincial Key Laboratory of Metabolic Liver Diseases, Jilin University, Changchun, Jilin, China.
J Virol. 2025 Sep 23;99(9):e0119825. doi: 10.1128/jvi.01198-25. Epub 2025 Sep 10.
Cholesterol 25-hydroxylase (CH25H), an interferon-stimulated gene (ISG), has been implicated in broad-spectrum antiviral immunity. Here, we identify CH25H as a potent suppressor of hepatitis B virus (HBV) replication that significantly outperforms IFN-α in reducing HBV DNA, pregenomic RNA (pgRNA), HBsAg, and HBeAg, without inducing cytotoxicity. However, CH25H is weakly expressed in hepatocytes and only modestly induced by type I interferon. We found that CH25H expression is tightly controlled by microRNAs, especially miR-7705, which is induced by IFN-α in a STAT1-dependent manner. miR-7705 directly targets the 3'UTR of CH25H, suppressing its expression and enhancing HBV replication. Knockdown of miR-7705 restores CH25H levels, enhances IFN-induced antiviral responses, and suppresses HBV replication in both transient transfection and infection models. Mechanistically, miR-7705 overexpression nullifies CH25H-mediated suppression of HBV, whereas this effect is abolished in CH25H-knockout cells, confirming the specificity of the miR-7705-CH25H axis. Furthermore, we demonstrate that this regulatory axis also governs CH25H-mediated restriction of RNA viruses, including EV71 and CVB3, suggesting its broad antiviral relevance. Importantly, antagonizing miR-7705 enhances the efficacy of IFN-based therapy against both DNA and RNA viruses. These findings reveal miR-7705 as a negative regulator of CH25H and position the miR-7705-CH25H axis as a promising target to improve antiviral immunity.
This study highlights the critical role of miR-7705 in regulating the antiviral effects of interferon (IFN) therapy, particularly in the context of chronic HBV infection. By identifying miR-7705 as a key modulator of CH25H, a protein essential for controlling HBV replication, our research provides new insights into the mechanisms that limit the effectiveness of IFN treatment. Targeting miR-7705 could improve the efficacy of IFN-based therapies, offering a potential strategy to better manage HBV and other viral infections. This research paves the way for developing adjunctive treatments that enhance the body's natural antiviral responses.
