Objective To investigate the role of hepatic stellate cells HSCs in hepatocellular carcinoma HCC . Method The study analyzed data from the GEO database GSE25097 to identify changes in HSCs expression in patients with liver cirrhosis and HCC. The LX2 cell line representing HSCs and the HepG2 cell line representing HCC were selected for in vitro experiments. The experimental group involved Transwell co-culture while the control group consisted of HepG2 cells cultured alone. After three days of culture second - generation sequencing was performed. The mechanism of HSCs ' effect on HCC was further explored using bioinformatics and flow cytometry. Result Analysis of GSE25097 data revealed a significant increase in HSCs expression in patients with liver cirrhosis P<0. 05 while a significant decrease was observed in HCC patients compared to those with cirrhosis P<0. 05 . Sequencing results indicated that the differentially expressed genes between the two groups were primarily involved in metabolism and apoptosis. Metabolism - related significantly different genes were mainly enriched in metabolic pathways and the AMPK signaling pathway with key genes including SLC11A1 GPX3 and PFKP. Apoptosis -related significantly different genes were enriched in cancer pathways and the TNF signaling pathway with key genes including PDGFB IGFBP3 FOS and DUSP1. Phenotypic experiments demonstrated that LX2 could inhibit HepG2 proliferation P<0. 05 and promote HepG2 apoptosis P<0. 05 P<0. 01 . Mitochondrial membrane potential experiments also confirmed that LX2 could promote HepG2 apoptosis P<0. 01 . Conclusion HSCs exert a direct inhibitory effect on HCC primarily by disrupting tumor cell metabolism and promoting apoptosis.