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Hyperactivation of the cyclic‐GMP‐AMP synthase (cGAS)–stimulator of interferon genes (STING) signalling pathway has been shown to be associated with the development of a variety of inflammatory diseases, and the discovery of an inhibitor of the cGAS‐STING signalling pathway holds great promise in the therapeutic interventions. Epimedium flavonoid (EF), a major active ingredient isolated from the medicinal plant Epimedium, has been reported to have good anti‐inflammatory activity, but its exact mechanism of action remains unclear. In the present study, we found that EF in mouse bone marrow‐derived macrophages (BMDMs), THP‐1 (Tohoku Hospital Pediatrics‐1) as well as in human peripheral blood mononuclear cells (hPBMC) inhibited the activation of the cGAS‐STING signalling pathway, which subsequently led to a decrease in the expression of type I interferon (IFN‐β, CXCL10 and ISG15) and pro‐inflammatory cytokines (IL‐6 and TNF‐α). Mechanistically, EF does not affect STING oligomerization, but inhibits the formation of functional STING signalosome by attenuating the interaction of interferon regulatory factor 3 (IRF3) with STING and TANK‐binding kinase 1 (TBK1). Importantly, in vivo experiments, EF has shown promising therapeutic effects on inflammatory diseases mediated by the cGAS‐STING pathway, which include the agonist model induced by DMXAA stimulation, the autoimmune inflammatory disease model induced by three prime repair exonuclease 1 (Trex1) deficiency, and the non‐alcoholic steatohepatitis (NASH) model induced by a pathogenic amino acid and choline deficiency diet (MCD). To summarize, our study suggests that EF is a potent potential inhibitor component of the cGAS‐STING signalling pathway for the treatment of inflammatory diseases mediated by the cGAS‐STING signalling pathway. [ABSTRACT FROM AUTHOR]