Dynamic zonal identity is a functional determinant of liver disease

RIZLiver infers a progressive loss of zone-3 metabolic identity with advancing stages of MASLD, consistently across independent patient cohorts, without using spatial coordinates.

• Why it matters: Zonal identity defines hepatic functional division, but its disease-linked remodeling and therapeutic potential have been unclear.
• What they did: The authors built RIZLiver, a Bayesian framework that infers zonal identity from gene expression alone, and validated it in independent MASLD patient cohorts; mouse models then tested how perturbing zonal identity alters diet-induced metabolic injury.
• The result: Zone-3 identity loss is linked to adaptive lipid utilization via lower case beta-catenin and PPARalpha, CTNNB1-mutated HCC shows enriched zone-3 and lipid-oxidative phenotypes, and restoring zone-3 or targeting PPARalpha yields therapeutic benefit in MASLD and CTNNB1-mutated HCC.

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