EMP1+ hepatic stellate cells drive hepatic fibrosis progression to hepatocellular carcinoma and predict prognosis

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 liver failure and 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 single-cell sequencing analysis and bulk sequencing analysis to identify genes, cellular subpopulations, and signalling pathways that are closely related to and highly expressed in hepatic fibrosis and HCC. On this basis, clinical prediction models and prognostic genes were constructed and validated by combining single-cell analysis with bulk differential gene analysis in the TCGA database, using 101 machine learning approaches, combined with survival analysis tools, and making full use of clinical data. In addition, the expression heterogeneity of core prognostic genes and their correlation with prognostic outcomes were explored in depth, and new targeted therapeutic modalities were sought with the help of comprehensive and systematic network pharmacological analyses to identify drugs that can target core prognostic genes. Results We identified 45 HSC-associated pathogenic genes and an EMP1 + HSC subpopulation, along with their regulatory signaling pathways linked to energy metabolism, cell adhesion, and extracellular matrix organization. These pathways were found to contribute to hepatic fibrosis and HCC progression. Subsequently, we validated four core prognostic genes (NPY1R, CTHRC1, IGFBP3, and ADH1B) and analyzed the heterogeneity of their expression patterns, demonstrating their correlation with hepatic fibrosis progression and HCC prognosis. Finally, through a systematic screening of bioactive compounds from traditional Chinese medicine (TCM) with potential anti-liver disease effects, we determined that Salvia miltiorrhiza(Danshen) specifically interacts with these core prognostic targets, offering a novel therapeutic strategy for hepatic fibrosis and HCC. Conclusion This integrative study establishes EMP1 as a reliable biomarker for activated HSCs and identifies four core prognostic genes (NPY1R, CTHRC1, IGFBP3, and ADH1B) that play critical roles in the fibrosis-to-HCC progression and demonstrate significant clinical relevance to long-term patient outcomes. Our findings provide novel mechanistic insights into hepatic fibrogenesis and HCC development, while simultaneously revealing Salvia miltiorrhiza (Danshen) as a promising therapeutic agent targeting these key molecular pathways. These discoveries offer a dual advancement in both diagnostic precision and treatment strategy for hepatic fibrosis and HCC.