Bardoxolone methyl exerts an inhibitory effect on respiratory syncytial virus infection by downregulating IL-6 via the IKKβ/NF-κB signaling pathway

ABSTRACT Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections in infants, older adults, and immunocompromised individuals, but therapeutic options for active infection remain limited. Interleukin-6 (IL-6) contributes to RSV replication and RSV-induced inflammation, and the IKKβ/NF-κB pathway is a major regulator of IL-6 expression. Bardoxolone methyl (BXM) was identified by network medicine as a potential anti-RSV compound, with molecular docking suggesting interactions with the IKKβ/NF-κB pathway. We investigated whether BXM inhibits RSV infection through modulation of the IKKβ/NF-κB/IL-6 axis in RSV-infected BEAS-2B cells and BALB/c mice. RSV infection increased IL-6 expression and activated IKKβ/NF-κB signaling, whereas IL-6 knockdown reduced viral replication and inflammatory mediator expression. BXM significantly suppressed RSV replication, as shown by RT-qPCR, TCID₅₀, plaque reduction assays, and Western blotting, and decreased IL-6 expression in vitro . Mechanistically, BXM attenuated RSV-induced phosphorylation of IKKβ and NF-κB. The IKKβ inhibitor TPCA-1 produced similar inhibitory effects, whereas recombinant human IL-6 add-back partially restored inflammatory mediator expression in BXM-treated RSV-infected cells. In mice, BXM reduced lung viral titers, RSV-F expression, IL-6 expression, IKKβ/NF-κB activation, and RSV-induced lung injury. These findings suggest that BXM suppresses RSV replication and inflammation, at least in part, by modulating the IKKβ/NF-κB/IL-6 axis, supporting its potential as a therapeutic candidate for RSV infection. IMPORTANCE Respiratory syncytial virus (RSV) is a major cause of respiratory illness, especially in infants, older adults, and people with weakened immune systems. Although preventive strategies are available for some high-risk groups, treatment options for active RSV infection remain limited. This study identifies bardoxolone methyl (BXM) as a potential anti-RSV compound and shows that it can reduce both viral replication and virus-induced inflammation in cell and mouse models. Importantly, our findings suggest that BXM acts, at least in part, by reducing IL-6-related inflammatory signaling, which is closely associated with RSV disease severity. These results provide experimental evidence supporting BXM as a promising candidate for further development against RSV infection and offer insight into a potential host-targeted therapeutic strategy.