Repurposing oxiconazole to inhibit STING trafficking via OSBP and alleviate autoimmune pathology in Trex1−/− mice

The cGAS-STING pathway is a critical component of the innate immune response to cytosolic DNA, driving the production of type I interferons (IFNs) and pro-inflammatory cytokines. However, excessive activation of this pathway is associated with various autoimmune and inflammatory diseases. In this study, we evaluated the regulation of FDA-approved azole antifungal drugs on the cGAS-STING pathway. Among these drugs, oxiconazole, miconazole, and itraconazole demonstrate significant inhibitory effects, with oxiconazole showing the strongest activity. Our data demonstrates that oxiconazole significantly suppressed type I IFN production and downstream inflammatory responses in macrophages and fibroblasts stimulated with synthetic DNA or infected with HSV-1. Mechanistically, oxiconazole hindered STING trafficking via oxysterol-binding protein OSBP. Using the Listeria monocytogenes infection model and the Trex1^−/− mouse disease model, both representing in vivo models of inflammation driven by excessive cGAS-STING activation, we demonstrate that oxiconazole enhanced bacterial clearance and reduced tissue damage in the Listeria monocytogenes infection model. Moreover, oxiconazole treatment significantly alleviated multi-organ inflammation and normalized aberrant IFN responses in the Trex1^−/− autoimmune disease mouse model. These findings highlight the potential of oxiconazole as a promising therapeutic agent for STING-driven autoimmune and inflammatory diseases.