Dihydrotanshinone I, a main compound of Salvia miltiorrhiza, alleviates autoimmune and inflammatory diseases by directly targeting IRF3

IF 6.7 1区医学 Q1 CHEMISTRY, MEDICINAL

Phytomedicine Pub Date : 2025-06-18 DOI:10.1016/j.phymed.2025.157005

Wei Shi , Jincai Wen , Yuan Gao , Tingting Liu , Hui Li , Huijie Yang , Jia Zhao , Ziying Wei , Chengwei Li , Qing Yao , Xiaohe Xiao , Zhaofang Bai

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引用次数: 0

Abstract

Background

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.

Methods

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.

Results

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.

Conclusion

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.

Abstract Image

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二氢丹参酮I是丹参的主要化合物，可直接靶向IRF3缓解自身免疫性和炎症性疾病

干扰素调节因子3 （IRF3）是免疫系统保护宿主免受攻击的重要组成部分，但过度激活IRF3会导致I型干扰素、干扰素刺激基因（ISGs）和促炎因子的释放，与多种炎症性疾病密切相关。因此，抑制IRF3的异常激活可以应用于炎症性疾病的治疗，具有广阔的应用前景。方法采用dna或RNA诱导ⅰ型干扰素和促炎细胞因子的释放，采用细胞模型或多种小鼠模型评价丹参主要活性成分二氢丹参酮1 （DHT）的体内外抗炎作用。机制上，通过检测IRF3和P65核易位、STING寡聚化和干扰素基因刺激因子(STING)-或线粒体抗病毒信号蛋白(MAVS)- tank结合激酶1 (TBK1)-IRF3复合物的表达来评估DHT抑制I型干扰素和促炎细胞因子的机制。结果丹参dht是一种有效成分，能有效抑制WT或Trex1-/-小鼠THP-1和BMDMs中干扰素-β (IFN-β)、ISGs和促炎因子的异常分泌。从机制上看，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，影响STING向IRF3募集。值得注意的是，DHT对irf3介导的炎症性疾病，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NASH具有良好的治疗效果。结论DHT是一种新型的I型干扰素和促炎细胞因子的抑制剂，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。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Phytomedicine 医学-药学

CiteScore

10.30

自引率

5.10%

发文量

670

审稿时长

91 days

期刊介绍： Phytomedicine is a therapy-oriented journal that publishes innovative studies on the efficacy, safety, quality, and mechanisms of action of specified plant extracts, phytopharmaceuticals, and their isolated constituents. This includes clinical, pharmacological, pharmacokinetic, and toxicological studies of herbal medicinal products, preparations, and purified compounds with defined and consistent quality, ensuring reproducible pharmacological activity. Founded in 1994, Phytomedicine aims to focus and stimulate research in this field and establish internationally accepted scientific standards for pharmacological studies, proof of clinical efficacy, and safety of phytomedicines.