GRID2, RNF186, and SLC4A10 were identified as independent prognostic genes, with RNF186 promoting HCC cell proliferation in a SESN2-dependent manner.<h4>Conclusion</h4>This prognostic model provides new insights into precision medicine and immunotherapy for HCC, highlighting the potential clinical significance of RNF186 as a therapeutic target. Here, SESN2 is linked to hepatocellular carcinoma.