Identification of prognosis-related metabolism genes in hepatocellular carcinoma: constructing a multi-gene model for...

Hepatocellular carcinoma (HCC) is a heterogeneous malignancy with poor prognosis. This study identifies metabolism-related genes (MRGs) associated with HCC prognosis, develops a multi-gene prognostic model based on metabolic reprogramming and immune escape, and evaluates their roles in the tumor microenvironment (TME) to guide diagnosis and treatment.

Transcriptomic and clinical data from HCC patients were analyzed using public databases (TCGA). MRGs linked to HCC staging and prognosis were identified. Weighted gene co-expression network analysis (WGCNA) detected metabolic gene modules associated with tumor progression. A multi-gene prognostic model was built using LASSO and random survival forests (RSF). Model performance was evaluated with Kaplan-Meier analysis, ROC curves, and Nomogram. Single-cell analyses explored metabolic interactions, and enrichment and mutation analyses assessed key genes' significance. PCR validated gene expression.

A total of 374 metabolism-related genes were linked to HCC staging. A prognostic model with eight key genes (UCK2, CAD, NUDT1, PIGU, IVD, CAT, ALDH6A1, SLC2A2) showed strong predictive performance across TCGA, ICGC, and GEO cohorts. Low-risk patients had significantly better survival (5-year survival prediction AUC of 0.75). PCR validation confirmed differential expression: UCK2, CAD, NUDT1, and PIGU were upregulated, while IVD, CAT, ALDH6A1, and SLC2A2 were downregulated. Immune infiltration analysis indicated an accumulation of immunosuppressive cells in the high-risk group, whereas the low-risk group exhibited an immune-active phenotype characterized by elevated infiltration of effector cells. Single-cell analysis uncovered metabolic-immune interactions in the TME. Gene mutation analysis showed frequent mutations in the high-risk group, linked to invasiveness and treatment resistance.

This study identifies key metabolism-related genes linked to HCC prognosis and develops a multi-gene prognostic model. Our findings highlight the roles of metabolic reprogramming and immune escape in HCC, providing a foundation for future immune and metabolic interventions.