A discovery of Clinically Approved TGP capsule alleviates cGAS-STING-mediated diseases by blocking STING-IRF3 interaction

In the context of autoimmune and inflammatory illnesses, the cyclic GMP-AMP synthase (cGAS) stimulator of interferon gene signaling (STING) has been extensively identified and verified. Unfortunately, few drugs had been approved to treat diseases or disorders linked to the cGAS-STING signaling system in clinic. Total Glucosides of Paeony (TGP) Capsule is a commonly used clinical drug for the treatment of rheumatoid arthritis (RA). In our research, we discovered that TGP capsule significantly inhibited the activation of the cGAS-STING signaling pathway induced by various cGAS-STING agonists in both mouse bone marrow-derived macrophages (BMDMs) and Tohoku Hospital Pediatrics-1 (THP-1) cells, accompanied by suppressing the phosphorylation of interferon regulatory factor 3 (IRF3) or the expression of interferon-beta (IFN-β), C-X-C motif chemokine ligand 10 (CXCL10) as well as inflammatory factors such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Mechanistically, the TGP capsule attenuated the interaction of STING-IRF3, exerted no influence on the oligomerization of STING, and ultimately blocked the activation of downstream signaling pathways. In vivo experiments, TGP capsule inhibited the initiation of the cGAS-STING pathway induced by the STING agonist dimethylxanthenone-4-acetic acid (DMXAA) and showed promising therapeutic effects in a lipopolysaccharide (LPS) and D-galactosamine (D-GalN)-induced model of acute liver injury. Overall, our work demonstrated that TGP capsule is a promising inhibitor of the cGAS-STING pathway and provided evidence that TGP capsule could be a treatment strategy for inflammatory and autoimmune diseases caused by the cGAS-STING pathway.