BackgroundAberrant activation of -catenin signaling by both WNT-dependent and WNT-independent pathways has been demonstrated in asthmatic airways, which is thought to contribute critically in remodeling of the airways. Yet, the exact role of -catenin in asthma is very poorly defined. As we have previously reported abnormal expression of -catenin in a toluene diisocyanate (TDI)-induced asthma model, in this study, we evaluated the therapeutic efficacy of two small molecules XAV-939 and ICG-001 in TDI-asthmatic male BALB/c mice, which selectively block -catenin-mediated transcription. MethodsMale BALB/c mice were sensitized and challenged with TDI to generate a chemically induced asthma model. Inhibitors of -catenin, XAV-939, and ICG-001 were respectively given to the mice through intraperitoneally injection. ResultsTDI exposure led to a significantly increased activity of -catenin, which was then confirmed by a luciferase assay in 16HBE transfected with the TOPFlash reporter plasmid. Treatment with either XAV-939 or ICG-001 effectively inhibited activation of -catenin and downregulated mRNA expression of -catenin-targeted genes in TDI-asthmatic mice, paralleled by dramatically attenuated TDI-induced hyperresponsiveness and inflammation of the airway, alleviated airway goblet cell metaplasia and collagen deposition, decreased Th2 inflammation, as well as lower levels of TGF1, VEGF, HMGB1, and IL-1. ConclusionThe results showed that -catenin is a principal mediator of TDI-induced asthma, proposing -catenin as a promising therapeutic target in asthma.