Shi Wei, Wen Jincai, Gao Yuan, Liu Tingting, Li Hui, Yang Huijie, Zhao Jia, Wei Ziying, Li Chengwei, Yao Qing, Xiao Xiaohe, Bai Zhaofang
Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, PR China; School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, PR China.
Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, PR China.
Phytomedicine. 2025 Sep;145:157005. doi: 10.1016/j.phymed.2025.157005. Epub 2025 Jun 18.
Interferon regulatory factor 3 (IRF3) is an essential component of the immune system to protect the host from aggression, but excessive IRF3 activation leads to the release of type I interferon, interferon-stimulated genes (ISGs) and pro-inflammatory factors, which closely linked to multiple inflammatory diseases. Therefore, suppression of aberrant activation of IRF3 can be applied to the therapy of inflammatory diseases and have promising applications.
DNA or RNA can induce the release of type I interferon and pro-inflammatory cytokines, and cell models or multiple mice models were used to assess the anti-inflammatory potential of Dihydrotanshinone 1 (DHT), the main active component of Salvia miltiorrhiza, in vivo and in vitro. Mechanistically, IRF3 and P65 nuclear translocation, STING oligomerization and stimulator of interferon genes (STING)- or mitochondrial antiviral signaling protein (MAVS)-TANK-binding kinase 1 (TBK1)-IRF3 complex expression were detected to evaluate the mechanisms of DHT on the inhibition of type I interferon and pro-inflammatory cytokines.
DHT, an active ingredient isolated from Salvia miltiorrhiza, was effective in suppressing the aberrant secrection of interferon-β (IFN-β), ISGs and pro-inflammatory cytokines in THP-1 and BMDMs in WT or Trex1 mice. Mechanistically, DHT have no influence on the interaction of STING-TBK1, IRF3-TBK1 and MAVS-TBK1, but directly binds to IRF3 and affects the recruitment of STING to IRF3. Significantly, DHT has promising therapeutic effects on IRF3-mediated inflammatory diseases, including Trex1 deficiency-related systemic inflammatory response, obesity-induced insulin resistance, and NASH.
In conclusion, DHT, a novel inhibitor of the production of type I interferon and pro-inflammatory cytokines, is a potential candidate for the therapeutic of IRF3-driven autoimmune and inflammatory diseases.
干扰素调节因子3（IRF3）是免疫系统保护宿主免受侵害的重要组成部分，但IRF3过度激活会导致I型干扰素、干扰素刺激基因（ISGs）和促炎因子的释放，这与多种炎症性疾病密切相关。因此，抑制IRF3的异常激活可用于炎症性疾病的治疗，并具有广阔的应用前景。
DNA或RNA可诱导I型干扰素和促炎细胞因子的释放，利用细胞模型或多种小鼠模型在体内和体外评估丹参主要活性成分二氢丹参酮1（DHT）的抗炎潜力。从机制上讲，检测IRF3和P65核转位、STING寡聚化以及干扰素基因刺激物（STING）或线粒体抗病毒信号蛋白（MAVS）-TANK结合激酶1（TBK1）-IRF3复合物的表达，以评估DHT抑制I型干扰素和促炎细胞因子的机制。
从丹参中分离出的活性成分DHT可有效抑制野生型或Trex1小鼠的THP-1细胞和骨髓来源的巨噬细胞（BMDMs）中干扰素-β（IFN-β）、ISGs和促炎细胞因子的异常分泌。从机制上讲，DHT对STING-TBK1、IRF3-TBK1和MAVS-TBK1的相互作用没有影响，但直接与IRF3结合并影响STING向IRF3的募集。值得注意的是，DHT对IRF3介导的炎症性疾病具有良好的治疗效果，包括Trex1缺乏相关的全身炎症反应、肥胖诱导的胰岛素抵抗和非酒精性脂肪性肝炎（NASH）。
总之，DHT是一种新型的I型干扰素和促炎细胞因子产生抑制剂，是治疗IRF3驱动的自身免疫性和炎症性疾病的潜在候选药物。
