Dynamic regulatory mechanism of cholesterol 25-hydroxylase-mediated antiviral response in RNA virus infections

Abstract

Due to their high mutation rates and adaptability, RNA viruses pose a persistent threat to public health. Cholesterol-25-hydroxylase (CH25H), an interferon-stimulated gene (ISG), produces 25-hydroxycholesterol (25HC), which plays a pivotal role in host defense against RNA virus infections. However, infection outcomes are determined by the dynamic interplay between viral infection and host immune defense, including cholesterol metabolism mediated by CH25H/25HC axis. This review aims to comprehensively elucidate the mechanisms underlying the interaction between CH25H/25HC and RNA viruses. We summarize recent advances in understanding the antiviral mechanisms of CH25H/25HC against RNA viruses, highlighting the central role of CH25H and its metabolite 25HC in inhibiting viral replication and regulating immune cell function. Furthermore, we discuss how RNA viruses evade host immune surveillance through strategies such as gene mutation, suppression of immune pathways, and interference with CH25H expression or function. Moreover, we emphasize endolysosomal cholesterol homeostasis as a host determinant of RNA virus entry, endosomal escape, trafficking, and replication, and discuss cholesterol-modulating host-directed therapies as complementary strategies to direct-acting antivirals. The findings indicate that dynamic regulation of CH25H and its metabolite 25HC is crucial for maintaining a balanced innate immune response against RNA viruses. This review comprehensively elucidated the dynamic molecular interactions between CH25H and RNA viruses, integrating recent research advances with a focus on molecular regulatory mechanisms. By synthesizing these findings, this review provided a mechanistic framework for understanding host–virus conflicts centered on cholesterol metabolism and proposed potential therapeutic strategies targeting this axis.