【Abstract】 Objective The present study was designed to elucidate the role of matrine (MAT) in modulating glucose and lipid metabolic disturbances and the epithelial-mesenchymal transition (EMT), with a view to attenuating cholestatic hepatic fibrosis (HF) following bile duct ligation (BDL) in rats. Methods A total of 24 healthy male Sprague-Dawley (SD) rats were randomly assigned to four experimental groups: the sham-operated control group (Sham group), the common bile duct ligation model group (BDL group), and two intervention groups receiving either a low dose (LMAT group, 50 mg/kg) or a high dose (HMAT group, 100 mg/kg) of the medical intervention. Histopathological changes and collagen deposition in liver tissues are evaluated via hematoxylin and eosin (H&E), Masson, and Sirius Red staining. Serum levels of alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bile acid (TBA),gamma-glutamyl transferase (GGT) and Triglyceride (TG) in each group of rats were determined using a fully automated biochemical analyzer. Immunohistochemical (IHC) staining determines the expression level of α-smooth muscle actin (α-SMA). The mRNA expression levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, glucose metabolism markers including glucose transporter 1 (GLUT1) and hexokinase 2 (HK2), and lipid metabolism markers including sterol regulatory element-binding protein 1c (SREBP1c), fatty acid synthase (FASN), peroxisome proliferator-activated receptor α (PPARα), and carnitine palmitoyltransferase 1A (CPT1A) are quantified using qRT-PCR. Western blot analysis measures the protein levels of TNF-α, IL-6, IL-1β, proliferating cell nuclear antigen (PCNA), cleaved caspase-3, B-cell lymphoma 2 (BCL-2), B-cell lymphoma 2-associated X protein (BAX), the epithelial marker E-cadherin, and the mesenchymal markers N-cadherin and vimentin. Results Compared with the Sham group, the BDL group showed more severe hepatic fibrosis, as evidenced by significantly increased serum levels of ALT, ALP,TBA, GGT and TG, a larger α-SMA-positive area in liver tissue, elevated mRNA and protein expression of TNF-α, IL-6, and IL-1β, increased protein expression of PCNA and cleaved caspase-3, and a reduced BCL-2/BAX ratio. (all P<0.05).Compared with the BDL group, MAT treatment effectively ameliorated liver injury and collagen deposition. Both the LMAT and HMAT groups exhibited reduced serum levels of ALT、ALP、TBA、GGT、TG and collagen accumulation, together with improved serum liver function, a smaller α-SMA-positive area, decreased mRNA and protein expression of TNF-α, IL-6, and IL-1β, reduced protein expression of PCNA and cleaved caspase-3, and an increased BCL-2/BAX ratio (all P<0.05). Furthermore, relative to the Sham group, E-cadherin protein expression is downregulated in the BDL group, while N-cadherin and vimentin expression is markedly upregulated. Concurrently, substantial glucose and lipid metabolism disorders occur in the BDL group, characterized by the sharp upregulation of GLUT1, HK2, SREBP1c, and FASN mRNA levels, alongside the significant suppression of PPARα and CPT1A mRNA levels (all P<0.05). Following low- and high-dose MAT intervention, these metabolic and EMT abnormalities are significantly reversed compared with the BDL group (all P<0.05). Conclusions Matrine attenuates hepatic fibrosis accompanied by the reversal of EMT and improvement of glucose and lipid metabolism disorders.