The origin of hepatocellular carcinoma (HCC) depends on the metabolic zonation of the liver, where different zones differ in metabolic functions.[1][2] The study showed that the zone-specific introduction of mutations in the Ctnnb1 and Arid2 genes, commonly co-mutated in HCC, determines the fate of premalignant cells according to their location and metabolic environment.[1][2] Ctnnb1/Arid2-driven tumors arose much more frequently in zone 3 than in zone 1 in aging mice.[1][2][3] The genes Gstm2 and Gstm3, enriched in zone 3, were essential for efficient initiation of HCC, in part by inhibiting ferroptosis.[1][2][3] These glutathione-S-transferases protect mutated cells from cell death caused by toxins and enable tumor formation.[3] Inhibiting Gstm2 and Gstm3 genetically or with drugs prevented the development of liver cancer.[3] Zonal determinants of HCC reveal the metabolic weaknesses of liver cancer.[1][2]