Human Liver Organoid Platforms for MASH Drug Discovery: Evaluating Immunometabolic Fidelity, Pharmacological Predictivity, and Translational Readiness

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of metabolic dysfunction-associated steatotic liver disease characterised by steatosis, inflammation, hepatocellular injury and fibrosis. Human liver organoid platforms offer a controllable system for modelling selected MASH-related processes and evaluating candidate therapeutics, but their performance varies across biological fidelity, pharmacological predictivity and translational readiness. This review evaluates three major platform types: pluripotent stem cell (PSC) - derived multicellular organoids, expandable hepatocyte organoids and assembled multicellular systems. Current evidence indicates that PSC-derived models provide the broadest representation of multicellular MASH phenotypes, hepatocyte organoids are particularly suitable for genetic and pharmacological screening, and assembled systems offer greater control over cell composition and experimental conditions. However, no single platform currently combines adult-like hepatic function, robust multicellular disease modelling, scalable screening and demonstrated clinical predictivity. Major limitations include immature cell states, donor and batch variability, and limited representation of perfusion, zonation and extrahepatic metabolism. Overall, liver organoids are best viewed as fit-for-purpose tools for mechanistic studies, target validation and early candidate evaluation, with future progress requiring improved standardisation, patient-tissue benchmarking and clinically relevant validation.