Background and PurposeStimulator of interferon response cGAMP interactor 1 (STING), a central hub protein of cyclic GMP‐AMP synthase (cGAS)–STING signalling pathway, has a crucial role in regulating type I interferons (IFNs) production and response. Recent studies indicate that excessive activation of STING is strongly associated with autoimmune diseases, including systemic lupus erythematosus (SLE). Searching immunomodulators that negatively regulate STING might greatly contribute to the suppression of autoimmunity.Experimental ApproachThe peripheral blood mononuclear cells (PBMCs) of SLE patients, Hela cells, L929 cells and bone marrow‐derived macrophages (BMDMs) from mice were used as in vitro models. While, Trex1 KO mouse autoimmune disease model was used as in vivo model. After treatment with cordycepin, a nucleoside from Cordyceps mushrooms, type I IFNs production and response were determined by western blotting, real‐time polymerase chain reaction (PCR), dual‐luciferase assay, enzyme‐linked immunosorbent assay (ELISA), haematoxylin–eosin staining and RNA‐seq.Key ResultsCordycepin inhibited type I IFNs production and response in human and murine systems following cGAS–STING signalling activation. Importantly, cordycepin markedly attenuates the autoinflammatory and autoimmune responses in Trex1 KO BMDMs and Trex1 KO mice. Furthermore, cordycepin effectively suppressed the production of type I IFNs and interferon‐stimulated genes (ISGs) in the PBMCs of SLE patients. Mechanistically, cordycepin promoted STING degradation via autophagy pathway upon DNA stimulation.Conclusion and ImplicationsThis study shows that cordycepin promotes STING autophagic degradation to alleviate autoimmunity upon DNA stimulation. Cordycepin might be a potential therapeutic candidate for alleviating aberrant type I IFNs in autoimmune and autoinflammatory diseases.
