DIDS modulates VDAC1 oligomerization to suppress intrinsic apoptosis and attenuates in vitro and in vivo RSV infection

Siyu Lin; Xiaotong Chen; Meihua Luo; Xiaolu Cui; You Dai; Zhen Sun; Guikang Wang; Hong Peng; Ping Ling; Jinlin Long; Huifang Zhou; Changlei Luo; Yan-Fei Qi; Ke Zhang; Yu-Si Luo

doi:10.1128/jvi.02200-25

DIDS modulates VDAC1 oligomerization to suppress intrinsic apoptosis and attenuates in vitro and in vivo RSV infection

J Virol. 2026 Feb 11:e0220025. doi: 10.1128/jvi.02200-25. Online ahead of print.

Authors

Siyu Lin^#¹, Xiaotong Chen^#¹, Meihua Luo¹, Xiaolu Cui¹, You Dai¹, Zhen Sun², Guikang Wang¹, Hong Peng³, Ping Ling⁴, Jinlin Long³, Huifang Zhou³, Changlei Luo³, Yan-Fei Qi⁵, Ke Zhang¹, Yu-Si Luo^{1

3

6}

Affiliations

¹ Guizhou Key Laboratory of Microbio and Infectious Disease Prevention & Control, Institute of Virology, The Key and Characteristic Laboratory of Modern Pathogenicity Biology, School of Basic Medicine, Guizhou Medical University, Guiyang, Guizhou, China.
² School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou National Laboratory, Guangzhou, Guangdong, China.
³ Emergency Department, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China.
⁴ PICU, Guiyang Maternal and Child Health Care Hospital, Guiyang, Guizhou, China.
⁵ Department of Pharmacology, College of Osteopathic Medicine, Duquesne University, Pittsburgh, Pennsylvania, USA.
⁶ Department of Emergency, Liupanshui Hospital of The Affiliated Hospital of Guizhou Medical University, Liupanshui, Guizhou, China.

^# Contributed equally.

PMID: 41670372
DOI: 10.1128/jvi.02200-25

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.IMPORTANCEThe study evaluates the antiviral activity of the VDAC1 inhibitor DIDS against respiratory syncytial virus (RSV), a major cause of lower respiratory tract infections worldwide. VDAC1 is identified as a key factor in RSV infection, with DIDS significantly inhibiting viral replication by blocking RSV-induced VDAC1 oligomerization in the mitochondrial membrane, suppressing mitochondrial apoptosis, and disrupting chloride ion flux. These findings establish that VDAC1-mediated regulation of anion homeostasis and subsequent mitochondrial-mediated apoptosis is a critical mechanism promoting RSV replication, providing a novel target for antiviral strategies.

Keywords: DIDS; RSV; VDAC1; apoptosis; in vitro and in vivo antivirus; oligomerization.