Background:Hepatocellular carcinoma (HCC) is a global health challenge with complex pathophysiology, characterized by high mortality rates and poor early detection due to significant tumor heterogeneity. Stemness significantly contributes to the heterogeneity of HCC tumors, and glycolysis is crucial for maintaining stemness. However, the predictive significance of glycolysis-related metabolic genes (GMGs) in HCC remains unknown. Therefore, this study aimed to identify critical GMGs and establish a reliable model for HCC prognosis.Methods:GMGs associated with prognosis were identified by evaluating genes with notable expression changes between HCC and normal tissues retrieved from the MsigDB database. Prognostic gene characteristics were established using univariate and multivariate Cox regression studies for prognosis prediction and risk stratification. The “CIBERSORT” and “pRRophetic” R packages were respectively used to evaluate the immunological environment and predict treatment response in HCC subtypes. The HCC stemness score was obtained using the OCLR technique. The precision of drug sensitivity prediction was evaluated using CCK-8 experiments performed on HCC cells. The miagration and invasion ability of HCC cell lines with different riskscores were assessed using Transwell and wound healing assays.Results:The risk model based on 10 gene characteristics showed high prediction accuracy as indicated by the receiver operating characteristic (ROC) curves. Moreover, the two GMG-related subgroups showed considerable variation in the risk of HCC with respect to tumor stemness, immune landscape, and prognostic stratification. Thein vitrovalidation of the model’s ability to predict medication response further demonstrated its reliability.Conclusion:Our study highlights the importance of stemness variability and inter-individual variation in determining the HCC risk landscape. The risk model we developed provides HCC patients with a novel method for precision medicine that enables clinical doctors to customize treatment plans based on unique patient characteristics. Our findings have significant implications for tailored immunotherapy and chemotherapy methods, and may pave the way for more personalized and effective treatment strategies for HCC.