Wen Jincai, Qin Shuanglin, Li Yurong, Zhang Ping, Zhan Xiaoyan, Fang Mingxia, Shi Ce, Mu Wenqing, Kan Wen, Zhao Jia, Hui Siwen, Hou Manting, Li Hui, Xiao Xiaohe, Xu Guang, Bai Zhaofang
School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China; Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China; China Military Institute of Chinese Materia, Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China.
Department of Hepatology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China; School of Pharmacy, Xianning Medical College, Hubei University of Science and Technology, Xianning, PR China.
Food Chem Toxicol. 2023 May;175:113732. doi: 10.1016/j.fct.2023.113732. Epub 2023 Mar 21.
In recent years, we have found that the dysregulation of the cyclic-GMP-AMP synthase (cGAS)‒stimulator of interferon genes (STING) pathway leads to the development of immune and inflammatory diseases, therefore, finding compounds that can specifically regulate this pathway is essential for effective regulation of the immune pathway for addressing inflammatory diseases. Licorice flavonoids (LFs), are active ingredients extracted from the Chinese herb licorice, which has been reported to have strong anti-inflammatory activity in previous studies. Here, we report that LFs inhibit the activation of the cGAS-STING pathway evidenced by the inhibition of the expression of type I interferons and related downstream genes such as interferon-stimulated gene 15 (ISG15) and C-X-C motif chemokine ligand 10 (CXCL10), as well as inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Notably, LFs markedly improve the LPS-induced acute lung injury by inhibiting the excessive activation of cGAS-STING signaling pathway. Mechanistically, LFs treatment leads to the blocking of 2'3'-cyclic GMP-AMP (cGAMP) synthesis resulting in an inhibition of the activation of the cGAS-STING pathway. Our results indicate that LFs is a specific inhibitor of the cGAS-STING pathway, which is suggested to be a potential candidate for the treatment of cGAS-STING pathway-mediated inflammatory diseases.
近年来，我们发现环磷酸鸟苷-腺苷酸合成酶（cGAS）-干扰素基因刺激因子（STING）信号通路的失调会导致免疫和炎症性疾病的发生，因此，找到能够特异性调节该信号通路的化合物对于有效调节免疫通路以治疗炎症性疾病至关重要。甘草黄酮（LFs）是从中药甘草中提取的活性成分，此前的研究报道其具有较强的抗炎活性。在此，我们报告LFs可抑制cGAS-STING信号通路的激活，这一作用通过抑制I型干扰素及相关下游基因如干扰素刺激基因15（ISG15）和C-X-C基序趋化因子配体10（CXCL10）的表达得以证实，同时也抑制了白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）等炎性细胞因子的表达。值得注意的是，LFs通过抑制cGAS-STING信号通路的过度激活，显著改善了脂多糖诱导的急性肺损伤。机制上，LFs处理导致2'3'-环磷酸鸟苷-腺苷酸（cGAMP）合成受阻，从而抑制了cGAS-STING信号通路的激活。我们的结果表明，LFs是cGAS-STING信号通路的特异性抑制剂，有望成为治疗cGAS-STING信号通路介导的炎症性疾病的潜在候选药物。
