Hot zones for liver cancer: metabolic zonation, ferroptosis, and the origins of HCC

Abstract 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, but whether cancer favors any particular zone has remained unclear. In a new study, Guo and colleagues use sophisticated mouse genetics to introduce cancer-driving mutations in specific liver zones. By combining this 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.