Objective To investigate the mechanism by which Huangqi (Astragali Radix)-Danshen (Salviae Miltiorrhizae Radix et Rhizoma) herb pair (HQ-DS) in treating hepatic fibrosis (HF) via regulating the endogenous retroviruses (ERVs)/retinoic acid-inducible gene I-like receptors (RLRs)/type I interferon (IFN-I) signaling pathway. Methods The components of HQ-DS extract and drug-containing serum were analyzed and identified using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A total of 48 male C57BL/6J mice were randomly divided into control group, model group, HQ-DS low-, medium-, high-dose (4.55, 9.10, 18.20 g/kg) groups and silymarin (100 mg/kg) group, with eight mice in each group. A mouse model of HF was established using carbon tetrachloride (CCl₄), and after drug intervention, liver function related indicators in serum were detected. The pathological changes of liver tissue through hematoxylin eosin (HE) staining, Masson and Sirius red staining were observed. Flow cytometry was used to detect macrophage infiltration in liver tissue. Western blotting was used to detect the expressions of fibrosis related proteins in liver tissue. High-throughput transcriptome sequencing was used to analyze changes in gene transcription levels in liver tissue. The expressions of factors related to the ERVs/RLRs/IFN-I signaling pathway in liver tissue were detected using qRT-PCR, Western blotting and ELISA. A HF model was established in Mavs^-/- mice and intervened with HQ-DS to verify the mechanism of HQ-DS’s anti-HF effect. In vitro experiments were conducted using CCK-8 assay to evaluate the effect of HQ-DS on the activity of iBMDM cells stimulated by lipopolysaccharides (LPS) and nigericin. Immunofluorescence detection of dsRNA expression was performed, qRT-PCR and Western blotting were used to further verify the inhibitory effect of HQ-DS on the activation of ERVs. Results Compared with control group, the body weight of mice in model group was increased slowly, with vacuolar degeneration and inflammatory cell infiltration in liver tissue, liver function related indicators in serum were significantly increased (P < 0.001), and the expressions of factors related to the ERVs/RLRs/IFN-I signaling pathway in liver tissue were significantly increased (P < 0.001). Compared with model group, HQ-DS and silymarin intervention significantly improved the slow growth of body weight in mice (P < 0.01, 0.001), significantly reduced the degree of vacuolar degeneration and inflammatory infiltration in liver tissue, significantly reduced liver function related indicators in serum (P < 0.01, 0.001), effectively alleviated the process of HF, and significantly reduced the expressions of factors related to the ERVs/RLRs/IFN-I signaling pathway in liver tissue (P < 0.05, 0.01, 0.001). Subsequent verification of the underlying mechanisms revealed that in Mavs^-/- mice, the elevation of pro-inflammatory factors induced by CCl₄ was markedly suppressed (P < 0.001), the mRNA expression levels of factors associated with the ERVs/RLRs/IFN-I signaling pathway were significantly downregulated (P < 0.001). However, following the administration of HQ-DS, there was no significant change in the mRNA expression levels of inflammatory factors and factors related to the ERVs/RLRs/IFN-I pathway. In cell experiments, compared with model group, HQ-DS significantly increased iBMDM cell viability (P < 0.001), reduced dsRNA accumulation, and downregulated the expressions of core genes in ERVs and IFN-I pathways (P < 0.05, 0.01, 0.001), while inhibited the expressions of key proteins [phosphorylated TANK binding kinase 1 (p-TBK1), phosphorylated interferon regulatory factor 3 (p-IRF3)] in RLRs pathway (P < 0.05, 0.01, 0.001). Conclusion HQ-DS alleviates inflammatory injury and ameliorates the progression of HF in mice by inhibiting ERVs/RLRs/IFN-I signaling pathway.

hepatic fibrosis  /  Astragali Radix-Salviae Miltiorrhizae Radix et Rhizoma herb pair  /  endogenous retrovirus  /  RLRs signaling pathway  /  type I interferons  /  macrophage