Total glucosides of paeony alleviates cGAS-STING-mediated diseases by blocking the STING-IRF3 interaction  

作　　者：XIU Ye WANG Sihao ZHANG Ping LI Chengwei WU Zhixin WEN Jincai XU Yingjie LV Guiji ZHAO Xiaomei DONG Xu CHEN Yichong LI Junjie WANG Yan ZOU Liang XIAO Xiaohe BAI Zhaofang 

机构地区：[1]School of Pharmacy,Fujian University of Traditional Chinese Medicine,Fuzhou 350122,China [2]Department of Hepatology,The Fifth Medical Center of PLA General Hospital,Beijing 100039,China [3]China Military Institute of Chinese Materia,Fifth Medical Center of Chinese PLA General Hospital,Beijing 100039,China [4]Department of Pharmacy,Medical Supplies Center of PLA General Hospital,Beijing 100039,China [5]School of Food and Biological Engineering,Chengdu University,Chengdu 610106,China [6]National Key Laboratory of Kidney Diseases,Chinese PLA General Hospital,Beijing 100039,China

出　　处：《Chinese Journal of Natural Medicines》2024年第5期402-415,共14页中国天然药物（英文版）

基　　金：This work was supported by the Natural Science Foundation of Beijing(No.7232321);the Cultivating and Improving the Service Ability of Traditional Chinese Medicine(No.2021ZY038);the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine(No.ZYYCXTD-C-202005);the State Key Program of National Natural Science of China(Nos.81930110,82230118)。

摘　　要：In the realm of autoimmune and inflammatory diseases,the cyclic GMP-AMP synthase(cGAS)stimulator of interferon genes(STING)signaling pathway has been thoroughly investigated and established.Despite this,the clinical approval of drugs targeting the cGAS-STING pathway has been limited.The Total glucosides of paeony(TGP)is highly anti-inflammatory and is commonly used in the treatment of rheumatoid arthritis(RA),emerged as a subject of our study.We found that the TGP markedly reduced the activation of the cGAS-STING signaling pathway,triggered by various cGAS-STING agonists,in mouse bone marrow-derived macrophages(BMDMs)and Tohoku Hospital Pediatrics-1(THP-1)cells.This inhibition was noted alongside the suppression of interferon regulatory factor 3(IRF3)phosphorylation and the expression of interferon-beta(IFN-β),C-X-C motif chemokine ligand 10(CXCL10),and inflammatory mediators such as tumor necrosis factor-alpha(TNF-α)and interleukin-6(IL-6).The mechanism of action appeared to involve the TGP’s attenuation of the STING-IRF3 interaction,without affecting STING oligomerization,thereby inhibiting the activation of downstream signaling pathways.In vivo,the TGP hindered the initiation of the cGAS-STING pathway by the STING agonist dimethylxanthenone-4-acetic acid(DMXAA)and exhibited promising therapeutic effects in a model of acute liver injury induced by lipopolysaccharide(LPS)and D-galactosamine(D-GalN).Our findings underscore the potential of the TGP as an effective inhibitor of the cGAS-STING pathway,offering a new treatment avenue for inflammatory and autoimmune diseases mediated by this pathway.

关 键 词：Total glucosides of gaeony cGAS-STING pathway Inflammation LPS/D-GalN STING inhibitor 

分 类 号：R285.5[医药卫生—中药学]