Introduction: Gain-of-function mutations in TMEM173 encoding STING (Stimulator of Interferon Genes) underlie a novel type I interferonopathy, minimally responsive to conventional immunosuppressive therapies and associated with high childhood morbidity and mortality.A newly emerging treatment strategy in STING-related inflammation aims to control interferon (IFN) signalling post-binding of the IFN receptor, by targeting JAK1/2.We hypothesized that inhibition of IFN production itself might represent an alternative therapeutic approach in this disease.Objectives: To evaluate the effect of BX795, a TBK1 inhibitor, on constitutive production of type I IFN in TMEM173-associated vasculopathy.Methods: Human embryonic kidney 293 cells (HEKs) transfected with wild-type (WT) or mutant STING, and peripheral blood mononuclear cells (PBMCs) from three patients were treated with BX795 2 μM.The effect of BX795 on TBK1 signalling cascade was assessed in HEKs by western blotting and IFNβ reporter assay.In patient cells, IFNα production was assessed by ultra-sensitive digital ELISA, STAT1 phosphorylation status by flow cytometry and RNA expression of IFNstimulated genes (ISG) by qPCR.Results: In HEKs, BX795 inhibited the phosphorylation of IRF3 and IFNβ promoter activity induced by cGAMP or mutant STING.In patient-derived PBMCs, exposure to BX795 inhibited IFNα production measured by digital ELISA, and was associated with a decrease of STAT1 phosphorylation and reduced ISG transcription.In addition, BX795 decreased the positive feedback loop of STING on the type I IFN pathway.Conclusion: Our findings demonstrate that inhibition of IFNα secretion is a potential approach to control disease-associated inflammation in patients with gain-of-function mutations in TMEM173, and may also be relevant in other monogenic type I interferonopathies.