Salvia miltiorrhiza water extract ameliorated cGAS-STING-mediated acute liver injury by blocking interaction between STING and TBK1

  • Chin Herb Med. 2025 Jan 7;17(4):768-778. doi: 10.1016/j.chmed.2025.01.002.
Chengwei Li  1  2  3  4 ,  Ran Xu  2  3 ,  Manlin Zhang  5 ,  Simin Chen  2  3 ,  Qing Yao  2  3 ,  Congyang Zheng  2  3 ,  Xianlin Wang  2  3 ,  Xinru Wen  2  3 ,  Xiaohe Xiao  2  3  4 ,  Yinghao Wang  1 ,  Zhaofang Bai  1  2  3  4
Affiliations
  • 1. School of Pharmacy, Fujian University of Traditional Chinese Medicine, Fuzhou 350122, China.
  • 2. Department of Hepatology, Fifth Medical Center of Chinese 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. State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Beijing 100700, China.
  • 5. Integrated Lab of Pathogenic Biology. Preclinical College, Dali University, Dali 671000, China.
PMID: 41399788 DOI: 10.1016/j.chmed.2025.01.002
Abstract

Objective: To investigate the potential of Salvia miltiorrhiza water extract (SMWE) as a modulator of the cGAS-STING signaling pathway, which is implicated in the pathogenesis of immune and inflammatory disorders, and to elucidate its underlying mechanism of action through in vitro and in vivo experiments.

Methods: The cGAS-STING signaling pathway was activated in bone marrow-derived macrophages (BMDMs), Tohoku hospital pediatrics-1 (THP-1) cells, and peripheral blood mononuclear cells (PBMCs). The effect of SMWE on the expression of phosphorylated interferon regulatory factor 3 (IRF3) and phosphorylated STING after aberrant activation of the cGAS-STING pathway was detected by immunoblotting. Subsequently, real-time quantitative PCR was performed to detect changes in the mRNA levels of interferon type I (IFN), interferon-stimulated genes and inflammatory factors. The effect of SMWE on STING oligomerisation and the interaction between STING, Tank Binding Kinase 1 (TBK1) and IRF3 was investigated by immunoblotting. A model of acute liver injury (ALI) caused by lipopolysaccharide/D-galactosamine (LPS/D-GaIN) was used to test the effects of SMWE on inflammation mediated by the cGAS-STING signaling cascade.

Results: SMWE significantly inhibited the phosphorylation of STING and IRF3, thereby suppressing the activation of the cGAS-STING signaling pathway. It also stopped the cGAS-STING pathway from working by stopping the production of type I interferons and interferon-stimulated genes, like interferon-stimulated gene 15 (ISG15) and C-X-C motif chemokine ligand 10 (CXCL10). SMWE also reduced the production of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). SMWE also significantly improved ALI resulting from LPS/D-GaIN by diminishing the hyperactivation of the cGAS-STING signalling pathway. Mechanistic analysis revealed that SMWE disrupted the interaction between STING and TBK1.

Conclusion: SMWE is a potent modulator of aberrant activation of the cGAS-STING pathway and is able to prevent and treat LPS/D-GaIN-induced ALI by inhibiting activation of the cGAS-STING pathway.

Keywords
IFN-β; STING; Salvia miltiorrhiza Bge.; acute liver injury; cGAS-STING; inflammation.
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