Study On Specific Inhibition Of CGAS-STING Signaling Pathway By Panax Notoginseng Extract

cGAS-STING signaling pathway recognizes pathogen DNA and activates innate immune response to protect the host from pathogenic infections,thus plays an important role in antimicrobial defenses.However,the presence of cytosolic DNA was considered as a danger signal to trigger innate immune response.Self-DNA was largely limited in the nucleus or mitochondria and will leak into the cytoplasm under certain pathological conditions.cGAS recognizes DNA in a sequence-independent manner.Abnormal accumulation of self-DNA in the cytoplasm activates cGAS-STING pathway and tigger immune response,resulting in autoimmune diseases.Panax notoginseng（Burkill）F.H.Chen ex C.H.is a famous Chinese herbal medicine with anti-inflammatory,anti-atherosclerosis,hemostasis and anti-tumor effects,as well as pharmacological effects on the immune system.Panaxynol and Panaxydol were identified as the effective components of Panax notoginseng,which play important roles in anti-tumor,anti-inflammatory,anti-depression,and obesity treatment.However,the role of Panax notoginseng or its extracts in the regulation of cGAS-STING signaling pathway and interferon responses remain unclear.Aim to explore the potential effect of Panax notoginseng in the regulation of cGAS-STING signaling pathway,we isolated and purified the effective components from Panax notoginseng and tested their effects on cGAS-STING pathway in vitro and in vivo.We first tested the ethanol and water extracts of Panax notoginseng on RAW264.7cells and determined the effective components.The compounds were determined as Panaxynol and Panaxydol by MS and NMR.Our results show that Panaxynol and Panaxydol specifically inhibited cGAS-STING pathway and have no effect on Toll-like receptor and RNA-pathway induced interferon responses.Furthermore,these compounds also inhibited the interferon production induced by self-DNA in Trex1^-/-mouse embryonic fibroblasts（MEFs）.Moreover,Panaxynol strongly inhibit interferon induction by STING agonist in wild-type mice.By using an Ifnβ^luc/luc reporter mice,we observed the signal of IFN-luciferase was significantly blocked by Panaxynol.In conclusion,our results suggest that Panaxynol and Panaxydol are the effective small molecular inhibitors of cGAS-STING pathway and interferon responses,therefore may be the drug candidate for autoimmune diseases.