Metabolic heterogeneity plays a key role in poor outcomes in malignant tumors, but its role in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, we aim to disentangle the metabolic heterogeneity features of HCC by developing a classification system based on metabolism pathway activities in high-throughput sequencing datasets. As a result, HCC samples were classified into two distinct clusters: cluster 1 showed high levels of glycolysis and pentose phosphate pathway activity, while cluster 2 exhibited high fatty acid oxidation and glutaminolysis status. This metabolic reprogramming-based classifier was found to be highly correlated with several clinical variables, including overall survival, prognosis, TNM stage, and 𝛼-fetoprotein (AFP) expression. Of note, activated oncogenic pathways, a higher TP53 mutation rate, and increased stemness were also observed in cluster 1, indicating a causal relationship between metabolic reprogramming and carcinogenesis. Subsequently, distinct metabolism-targeted therapeutic strategies were proven in human HCC cell lines, which exhibit the same metabolic properties as corresponding patient samples based on this classification system. Furthermore, the metabolic patterns and effects of different types of cells in the tumor immune microenvironment were explored by referring to both bulk and single-cell data. It was found that malignant cells had the highest overall metabolic activities, which may impair the anti-tumor capacity of CD8+ T cells through metabolic competition, and this provided a potential explanation for why immunosuppressive cells had higher overall metabolic activities than those with anti-tumor functions. Collectively, this study established an HCC classification system based on the gene expression of energy metabolism pathways. Its prognostic and therapeutic value may provide novel insights into personalized clinical practice in patients with metabolic heterogeneity.
Keywords: hepatocellular carcinoma; metabolic competition; metabolic heterogeneity; tumor microenvironment.