Liver Zonation Disruption Fuels Hepatocellular Carcinoma in Chronic Liver Disease

Hepatocellular carcinoma (HCC) arises almost exclusively in chronic liver disease (CLD), yet the classical etiological drivers of injury insufficiently explain why only a subset of patients progress to cancer. Here, we identify disruption of liver metabolic zonation, specifically, aberrant expansion of {beta}-catenin activity from pericentral to periportal territories as a previously unrecognized tumorigenic risk state that emerges across etiologically diverse CLDs. Using spatial transcriptomics and immunohistochemistry from murine liver disease followed by human sample validation, we demonstrate that MASLD/MASH, alcohol-associated hepatitis, viral hepatitis, and immune-mediated cholangiopathies share a striking periportal induction of pericentral {beta}-catenin target programs, indicating a conserved zonation disturbance independent of disease etiology. Since {beta}-catenin expansion occurs alongside inflammation, fibrosis, and metabolic dysfunction in human CLD, its direct oncogenic contribution remained unclear. To functionally isolate the tumorigenic consequence of zonation disruption itself from these confounding disease processes, we employed hepatocyte-specific deletion of ZNRF3 and RNF43--negative regulators that physiologically restrict {beta}-catenin to the pericentral zone. Lineage tracing demonstrates that ZNRF3/RNF43 deletion drives selective periportal hepatocyte proliferation, zonal reprogramming, and tumor initiation in a {beta}-catenin-dependent manner, establishing zonation disruption as a direct mechanistic driver of carcinogenesis. The resulting tumors exhibit a distinct metabolic and immunologic phenotype, including heightened mitochondrial respiration, preserved periportal identity, and T-cell competence, and correspond to a molecularly defined subset comprising 5-10% of human HCCs. Together, these findings reveal {beta}-catenin zonation expansion as a conserved and previously unrecognized HCC risk factor that mechanistically links chronic liver injury to malignant transformation. They further establish ZNRF3/RNF43 deletion as a tractable model of zonation-driven hepatocarcinogenesis and identify a distinct human HCC subtype with unique therapeutic vulnerabilities, opening new avenues for mechanism-based risk stratification, early detection and preventive therapeutic strategies in patients with chronic liver disease.