Abstract

Human respiratory syncytial virus (RSV) is a major pathogen causing acute lower respiratory tract infections in infants, young children, and elderly people worldwide. Viruses often hijack host cell ion channels to optimize their intracellular environment, positioning ion channel blockers as promising antiviral agents. On the outer mitochondrial membrane, voltage-dependent anion channel protein 1 (VDAC1) plays a crucial role in regulating mitochondrial pathway apoptosis and maintaining cellular homeostasis. This study systematically evaluates the antiviral activity of the VDAC1 inhibitor 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS), both in vitro and in vivo. The results demonstrate that VDAC1 is a key factor in RSV infection, and DIDS significantly inhibits viral replication. Functional intervention experiments show that DIDS effectively blocks RSV-induced VDAC1 oligomerization in the mitochondrial membrane, suppressing mitochondrial apoptosis and disrupting chloride ion (Cl−) flux, thereby inhibiting viral replication. Exogenous Cl− supplementation reverses these effects, further highlighting the critical role of VDAC1 in the life cycle of RSV. In conclusion, the antiviral effects and mechanistic insights of DIDS reveal that VDAC1 regulates mitochondrial-mediated apoptosis while also modulating anion homeostasis to promote viral replication. These findings provide a potential target and theoretical foundation for the development of novel antiviral strategies targeting mitochondrial ion channels.