Metabolomics Reveals the Anti-hepatic Fibrosis Mechanisms of Pueraria lobata (Willd.) Ohwi Extract and Potential Metabolites Alterations.

Liver fibrosis is a progressive disorder characterized by excessive extracellular matrix (ECM) accumulation, leading to impaired liver function and potentially cirrhosis. Pueraria lobata (Willd.) Ohwi, a traditional medicinal plant, has shown promise for hepatoprotection. In this study, we evaluated the antifibrotic effects of a 50% ethanol extract of Pueraria lobata (PUR50E) using integrated network pharmacology, metabolomics, and a CCl₄-induced mouse model of liver fibrosis. Network pharmacology analysis identified key PUR50E-associated targets involved in ECM organization, oxidative stress regulation, and TGF-β-related fibrogenic signaling pathways. PUR50E markedly reduced ECM markers, including α-SMA and fibronectin, and enhanced ECM remodeling through upregulation of MMP-3 and MMP-13. It also activated the Nrf2/HO-1 pathway to alleviate oxidative stress. Metabolomic profiling revealed key alterations, including reduced malate, fumarate, succinate, and isocitrate in the TCA cycle; decreased tryptophan, indole, and N-acetylserotonin with increased melatonin in tryptophan metabolism; and elevated glycine and homoserine in glyoxylate and dicarboxylate metabolism. These findings suggest that PUR50E mitigates liver fibrosis by promoting ECM degradation, enhancing antioxidant defense, and restoring metabolic homeostasis. The identified metabolites may serve as potential biomarkers and therapeutic targets, supporting the development of PUR50E as a promising multi-target natural therapy for liver fibrosis.