Hyperactivation of type I IFN signaling underlies a broad inflammatory program in VEXAS syndrome

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a severe systemic inflammatory disorder caused by somatic UBA1 mutations in hematopoietic cells [ 1 ]. Current treatments, including steroids, inhibitors of IL1, IL6, and JAK family kinases, hypomethylating agents, and allogeneic stem cell transplantation, offer only partial and inconsistent disease control, with significant toxicity and frequent treatment failure [ 2 , 3 , 4 , 5 , 6 ]. The absence of durable, well-tolerated therapies underscores the need to better define the autoinflammatory mechanisms driving VEXAS syndrome. Transcriptomic profiling of peripheral blood and bone marrow from VEXAS syndrome patients has consistently demonstrated marked upregulation of interferon (IFN) gene signatures [ 7 , 8 ]. The molecular mechanisms linking UBA1 mutations to IFN dysregulation remain unclear.