Dynamic zonal identity is a functional determinant of liver disease

Liver zonation demarcates functional division of labor within the hepatic lobule, yet how zonal identity is reshaped during disease remains poorly understood. We developed RIZLiver, a Bayesian framework that infers zonal identity from gene expression without spatial coordinates. RIZLiver identified progressive loss of zone-3 metabolic identity with advancing stages of metabolic dysfunction-associated steatotic liver disease (MASLD) across independent patient cohorts. Complementary mouse models reveal that perturbing zonal identity shifts susceptibility to diet-induced metabolic injury, linking zone-3 identity to adaptive lipid utilization through lower case beta-catenin and PPARalpha. CTNNB1-mutated hepatocellular carcinomas (HCC) showed an enriched zone-3 and lipid-oxidative phenotype, extending metabolic perturbations beyond MASLD. Pharmacologic reactivation of the zone-3 program shows a therapeutic effect in MASLD. Conversely, interfering with lipid-metabolic addiction in CTNNB1-mutated HCC by targeting PPARalpha; yielded a therapeutic benefit. Our findings identify zonation as a dynamic component of disease phenotype and its restoration as a potential therapy.