From the generation of cluster-specific GEMs for HCC, a four-gene signature consisting of PKM, folate metabolism gene MTHFS, G6PD and hypoxia-inducible factor 1 alpha (HIF1A) was proposed, indicating the activation of hypoxia response genes and the regulation of redox metabolism as targets of interest for the stratification and/or treatment of HCC patients (Figure 5A). This evidence concerns the gene MTHFS and hepatocellular carcinoma.