Abstract
BACKGROUND: Hepatic fibrosis is a pathological response to chronic liver injury that results in accumulation of extracellular matrix proteins leading to fibrous scarring, which can further lead to hepatocellular carcinoma (HCC). Although several clinical approaches have been applied to the diagnosis and treatment of hepatic fibrosis and HCC, the clinical prognosis and precision of targeted therapies still face great challenges. METHODS: In this study, we integrated multi-omics data to identify functional subpopulations of hepatic stellate cells (HSCs) closely associated with hepatic fibrosis and HCC. Based on this, differential genes derived from single-cell and bulk transcriptomic analyses were used to construct and validate a clinical prognostic model using 101 machine learning algorithms. Furthermore, we explored the expression heterogeneity of core prognostic genes (CPGs) and their correlation with clinical outcomes. A comprehensive network pharmacology analysis was also conducted to identify potential drugs targeting these genes, aiming to discover novel targeted therapeutic strategies. RESULTS: We identified a specific functional subpopulation of HSCs, characterized by EMP1 expression (EMP1 + HSCs), and elucidated the cellular functional pathways through which EMP1 + HSCs contribute to the progression from hepatic fibrosis to HCC. Subsequently, we identified and evaluated four CPGs-NPY1R, CTHRC1, IGFBP3, and ADH1B-for their expression heterogeneity and prognostic significance along the fibrosis-to-HCC axis, with biological validation at the proteomic level. Finally, network pharmacology analysis identified Salvia miltiorrhiza (Danshen) as a potential therapeutic agent targeting all four CPGs, offering a new direction for the treatment of hepatic fibrosis and HCC. CONCLUSION: This study, through the integration of multi-omics data, establishes EMP1 as a reliable marker of activated HSCs. The genes NPY1R, CTHRC1, IGFBP3, and ADH1B play critical regulatory roles and exhibit prognostic value in the progression from hepatic fibrosis to HCC. Our findings provide novel insights and therapeutic targets for the use of Salvia miltiorrhiza in treating hepatic fibrosis and HCC.