Dynamic zonal identity is a functional determinant of liver disease

Yasaka, T.; Inada, H.; Kim, C. K.; Singh-Varma, A.; Hu, S. P.; Lehrich, B.; Min, L.; Poddar, M.; Jain, A.; Meadows, V.; Rai, R.; Sipula, I.; Bello, F.; Gavlock, D.; Tanaka, Y.; Vandevender, A.; Singh, S.; Ren, Y.; Qin, F.-Y.; Uttam, S.; Bell, A.; Ma, X.; Raeman, R.; Liu, J.-J.; Liu, S.; Brown, J.; Miedel, M.; Jurczak, M. J.; Chiu, Y.-C.; Angers, S.; Khoo, N.; Monga, S. P.

doi:10.64898/2026.11.10.765616

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bioRxiv · 10.64898/2026.11.10.765616

Dynamic zonal identity is a functional determinant of liver disease

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Abstract

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.

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Yasaka, T., Inada, H., Kim, C. K., Singh-Varma, A., Hu, S. P., Lehrich, B., Min, L., Poddar, M., Jain, A., Meadows, V., Rai, R., Sipula, I., Bello, F., Gavlock, D., Tanaka, Y., Vandevender, A., Singh, S., Ren, Y., Qin, F.-Y., Uttam, S., Bell, A., Ma, X., Raeman, R., Liu, J.-J., Liu, S., Brown, J., Miedel, M., Jurczak, M. J., Chiu, Y.-C., Angers, S., Khoo, N., Monga, S. P.. 2026-11-12. Dynamic zonal identity is a functional determinant of liver disease. https://doi.org/10.64898/2026.11.10.765616

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