Hot Zones for Liver Cancer: Metabolic Zonation, Ferroptosis, and the Origins of HCC

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death and is often resistant to treatment, partly because it develops after decades of chronic injury in a metabolically heterogeneous organ. Anatomically, the liver is organized into lobules with three concentric zones, each with distinct gene expression and metabolic programs; however, it remains unclear whether cancer favors any particular zone. In a new study, Guo and colleagues use sophisticated mouse genetics to introduce cancer-driving mutations in specific liver zones. By combining this approach with spatial transcriptomics, they track premalignant hepatocytes within the tissue microenvironment. They discover that periportal zone 1 clones expand and persist more than the rare, relatively less fit clones in pericentral zone 3. Paradoxically, however, HCC mainly arises from zone 3 hepatocytes across multiple oncogenic models, revealing a striking disconnect between clonal expansion and tumorigenic potential. A functional screen of transcripts enriched in zone 3 identifies the glutathione S-transferases Gstm2 and Gstm3 as key factors in transformation. These enzymes maintain redox balance and suppress ferroptosis in early mutant cells. Genetic deletion, hepatocyte-specific knockdown, and irreversible chemical inhibition of GSTMs all increase oxidative stress and ferroptosis, preventing tumor formation. Ectopic expression of Gstm3 in zone 1 is sufficient to reprogram these cells into a cell-of-origin compartment. These findings define the "tumorigenic zonation" of the liver and suggest that targeting ferroptosis vulnerability could be a promising therapeutic strategy for HCC.