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

  • Phytomedicine. 2025 Jun 18:145:157005. doi: 10.1016/j.phymed.2025.157005.
Wei Shi  1 ,  Jincai Wen  2 ,  Yuan Gao  3 ,  Tingting Liu  2 ,  Hui Li  1 ,  Huijie Yang  2 ,  Jia Zhao  2 ,  Ziying Wei  2 ,  Chengwei Li  2 ,  Qing Yao  2 ,  Xiaohe Xiao  4 ,  Zhaofang Bai  5
Affiliations
  • 1. 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.
  • 2. Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, PR China.
  • 3. School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, PR China.
  • 4. Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, PR China; Military Institute of Chinese Materia, the Fifth Medical Centre, General Hospital of PLA, Beijing 100039, PR China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, PR China. Electronic address: [email protected].
  • 5. Department of Hepatology, Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, PR China; Military Institute of Chinese Materia, the Fifth Medical Centre, General Hospital of PLA, Beijing 100039, PR China; State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, PR China. Electronic address: [email protected].
PMID: 40609382 DOI: 10.1016/j.phymed.2025.157005
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.

Keywords
Dihydrotanshinone I; IRF3; Insulin resistance; Nonalcoholic steatohepatitis; TREX1 deficiency; Type I interferon.
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