Interferon-induced miR-7705 modulates the anti-virus activity of cholesterol 25-hydroxylase.

Abstract

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.

Importance: 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.