Carnosic Acid Directly Targets STING C‐Terminal Tail to Improve STING‐Mediated Inflammatory Diseases

Abstract cGAS (cyclic GMP‐AMP synthase)‐STING (stimulator of interferon genes) signaling plays a vital role in innate immunity, while its deregulation may lead to a wide variety of autoinflammatory and autoimmune diseases. It is essential to identify specifically effective lead compounds to inhibit the signaling. Herein, it is shown that carnosic acid (CA), an active ingredient of medicinal plant Rosmarinus officinalis L ., specifically suppressed cGAS‐STING pathway activation and the subsequent inflammatory responses. Mechanistically, CA directly bound to STING C‐terminal tail (CTT), impeded the recruitment of TANK‐binding kinase 1 (TBK1) onto STING signalosome, thereby blocking the phosphorylation of STING and interferon regulatory factor 3 (IRF3) nuclear translocation. Importantly, CA dramatically attenuated STING‐mediated inflammatory responses in vivo. Consistently, CA has a salient ameliorative effect on autoinflammatory disease model mediated by Trex1 deficiency, via inhibition of the cGAS‐STING signaling. Notably, the study further indicates that phenolic hydroxyl groups are essential for CA‐mediated STING inhibitory activity. Collectively, the results thus identify STING as one of the crucial targets of CA for mediating CA's anti‐inflammatory activity, and further reveal that STING CTT may be a novel promising target for drug development.