Diosmetin blocks type Ⅰ interferon signaling by metabolic control of phosphatidylethanolamine

Abstract Type I interferon (IFN-I) is essential in the development of Systemic Lupus Erythematosus (SLE) and many other autoimmune diseases. To explore the metabolic regulations of IFN-I signaling pathway, we conducted a high through-put screening of a small molecule library and identified diosmetin as a potent compound for blocking IFN-I signaling. We showed diosmetin functioned by preventing the alteration of cellular phosphatidylethanolamine and the spatiotemporal dynamics of IFNAR2 during the activation of IFN-I signaling pathway, and CYP1B1 was verified as the potential target of diosmetin. Further, diosmetin can ameliorate lupus-like autoimmune phenotypes in IFNα-accelerated NZB/NZW F1 lupus model and pristane-induced murine lupus model. Of note, diosmetin can block over-activated IFN-I signaling pathway in PBMCs from lupus patients by reducing the expression of CYP1B1. Our findings reveal a novel lipid metabolic regulation of IFN-I signaling and a potent alternative therapeutic target for autoimmune diseases with overactivated IFN-I signaling pathway.