Objective To investigate the therapeutic effect of ethanol extract of bran-fried Cangzhu (Atractylodis Rhizoma) (EBAR) on bile duct ligation-induced liver fibrosis in mice and explore the mechanism of its treatment for liver fibrosis from the perspective of regulating hepatic metabolites. Methods C57BL/6 mice were subjected to bile duct ligation to establish a liver fibrosis model and treated with EBAR for 14 d. Levels of liver function markers and inflammatory cytokines in serum were measured. The expressions of α-smooth muscle actin (α-SMA), collagen type I (COL1A1) and COL4A2 in liver tissues were detected by immunohistochemistry, qRT-PCR and Western blotting. JS1 cells were induced with transforming growth factor-β (TGF-β) to establish a hepatic stellate cell activation model. After EBAR intervention, the expressions of α-SMA, COL1A1, COL4A2 and tissue inhibitor of metalloproteinases 1 (TIMP1) were examined by immunofluorescence, qRT-PCR and Western blotting. Network pharmacology, molecular docking, molecular dynamics simulation and metabolomics were employed to investigate the potential mechanisms of EBAR against liver fibrosis, and key mechanisms were validated by Western blotting. Results In the liver fibrosis mouse model, EBAR significantly reduced liver index, serum liver function indicators and inflammatory cytokine levels (P < 0.05, 0.01), significantly inhibited the expressions of α-SMA, COL1A1 and COL4A2 in liver tissues (P < 0.05, 0.01), significantly alleviated hepatic fibrous tissue hyperplasia and collagen deposition and improved pathological damage in liver tissue. Network pharmacology analysis revealed that Atractylodis Rhizoma exerts anti-hepatic fibrotic effects primarily by regulating signaling pathways such as adenosine 5’-monophosphate-activated protein kinase (AMPK). Metabolomic analysis showed that EBAR affected the generation of various metabolites in liver tissues of liver fibrosis mouse model, particularly metabolites related to the citric acid cycle and fatty acid metabolism. Further mechanistic studies demonstrated that EBAR exerted anti-hepatic fibrotic effects by promoting AMPK phosphorylation (P < 0.05, 0.01) and activating AMPK/silent information regulator 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) signaling pathway. Conclusion EBAR exerts anti-fibrotic effects by activating AMPK/SIRT1/PGC-1α signaling pathway and regulating hepatic energy metabolism.

bran-fried Atractylodis Rhizoma  /  liver fibrosis  /  metabolomics  /  network pharmacology  /  molecular dynamics  /  citric acid cycle  /  fatty acid metabolism  /  atractylodin  /  atractylenolide I  /  atractylenolide II  /  atractylenolide III  /  AMPK/SIRT1/PGC-1α signaling pathway