From liver organoids to regulatory platforms for precision hepatology: Advances and challenges

Abstract

Liver organoids have rapidly advanced as human-relevant systems for modeling liver development, metabolic disease, and drug responses. Recent studies have established expandable adult hepatocyte organoids with sustained proliferative capacity, engineered induced pluripotent stem cell-derived organoids exhibiting metabolic zonation through controlled signaling gradients, and constructed multicellular assembloids that incorporate non-parenchymal cell types to recapitulate physiological periportal architecture and model cholestatic fibrotic microenvironments. These developments have enhanced scalability, structural organization, and disease modeling fidelity, supporting applications in translational research. Despite these advances, several challenges remain. Current evaluation of liver organoids largely relies on terminal functional outputs, while the upstream regulatory hierarchies that specify hepatic identity, zonation, and metabolic competence remain insufficiently reconstructed and validated. Limitations in long-term stability, spatial precision, and standardization further constrain predictive performance. This Review summarizes recent technological progress, discusses strategies to improve regulatory fidelity and functional benchmarking, and outlines future directions toward developing liver organoids as more reliable platforms for disease modeling and precision hepatology.