OBJECTIVE To investigate the effects and mechanisms of Sinisan against carbon tetrachloride (CCl₄)-induced liver fibrosis in mice using network pharmacology and metabolomics.

METHODS HPLC-Q-TOF was used for analysis of absorbed components of Sinisan. Network pharmacology was combined to predict its anti-hepatic fibrosis targets and perform pathway enrichment analysis. A CCl4-induced hepatic fibrosis mouse model was established and intervened with different doses of Sinisan. Liver injury, inflammation, collagen deposition, were assessed via serum biochemical indicators, liver histopathological staining (H&E, Masson, Sirius red), immunohistochemistry, ELISA, Western blot, and qPCR. Serum untargeted metabolomics was employed to screen differential metabolites and conduct pathway enrichment analysis.

RESULTS A total of 71 absorbed components and 130 shared drug-disease targets were identified. Pathway enrichment suggested the anti-fibrosis and anti-inflammatory mechanism may relate to signaling pathways such as AGE-RAGE and PI3K-Akt. Sinisan significantly alleviated hepatic pathological injury and fibrosis in mice, reduced serum levels of hepatic injury markers (ALT, AST, ALP) and fibrosis indicators, downregulated pro-inflammatory factors (TNF-α, IL-6, IL-8), upregulated the anti-inflammatory factor IL-10, and suppressed collagen synthesis. Sinisan reversed the abnormal metabolic profiles in fibrotic mice. Pathway enrichment of differential metabolites revealed arachidonic acid metabolism and linoleic acid metabolism as the core pathways mediating its effects.

CONCLUSION Sinisan ameliorates hepatic injury and fibrosis by regulating signaling pathways including AGE-RAGE and PI3K-Akt, suppressing hepatic stellate cell (HSC) activation and collagen deposition. Furthermore, it modulates core metabolic pathways involving arachidonic acid and linoleic acid to reshape the inflammatory microenvironment and inhibit extracellular matrix (ECM) deposition, exerting its anti-fibrotic effects.