Comprehensive Metabolic Profiling and Genome-wide Analysis Reveal Therapeutic Modalities for Hepatocellular Carcinoma

Understanding the details of metabolic reprogramming in hepatocellular carcinoma(HCC)is critical to improve stratification for therapy.Both multiomics analysis and cross-cohort validation were performed to investigate the metabolic dysregulation of 562 HCC patients from 4 cohorts.On the basis of the identified dynamic network biomarkers,227 substantial metabolic genes were identified and a total of 343 HCC patients were classified into 4 heterogeneous metabolic clusters with distinct metabolic characteristics:cluster 1,the pyruvate subtype,associated with upregulated pyruvate metabolism;cluster 2,the amino acid subtype,with dysregulated amino acid metabolism as the reference;cluster 3,the mixed subtype,in which lipid metabolism,amino acid metabolism,and glycan metabolism are dysregulated;and cluster 4,the glycolytic subtype,associated with the dysregulated carbohydrate metabolism.These 4 clusters showed distinct prognoses,clinical characteristics and immune cell infiltrations,which was further validated by genomic alterations,transcriptomics,metabolomics,and immune cell profiles in the other 3 independent cohorts.Besides,the sensitivity of different clusters to metabolic inhibitors varied depending on their metabolic features.Importantly,cluster 2 is rich in immune cells in tumor tissues,especially programmed cell death protein 1(PD-1)-expressing cells,which may be due to the tryptophan metabolism disorders,and potentially benefiting more from PD-1 treatment.In conclusion,our results suggest the metabolic heterogeneity of HCC and make it possible to treat HCC patients precisely and effectively on specific metabolic characteristics.