OBJECTIVE: Hepatocellular carcinoma (HCC), a lethal cancer with high global mortality, may be targeted through ferroptosis, an iron-dependent form of cell death. Despite its potential, the prognostic value of ferroptosis in HCC is underexplored. METHODS: Our study leveraged single-cell and bulk sequencing datasets to identify ferroptosis-related genes and developed a prognostic model via Cox and LASSO regression analyses. Survival and mutation analyses led to the creation of a nomogram for predicting patient prognosis. Furthermore, we investigated the role of GRINA, a ferroptosis-related gene, through functional assays, including cell proliferation, colony formation, and metastatic potential analyses. We also assessed mitochondrial abnormalities, intracellular iron, and ROS levels in GRINA-knockdown cells. RESULTS: The developed ferroptosis-related model classified HCC patients into risk groups, revealing notable survival disparities. High-risk patients presented increased immune checkpoint gene expression. The nomogram revealed robust prognostic accuracy. Additionally, we found that GRINA suppression reduced HCC cell proliferation, colony formation, and metastatic potential. Cells with GRINA knockdown presented mitochondrial abnormalities and increased intracellular iron and ROS levels. CONCLUSIONS: By analysing multiomics sequencing data, we established a connection between ferroptosis-related risk groups and the tumor immune microenvironment. These findings provide novel insights into the role of ferroptosis in HCC and suggest that GRINA inhibition is a potential therapeutic strategy, leading to mitochondrial damage and the induction of ferroptosis in HCC cell lines.