Hepatocyte Plasticity in Liver Health and Disease: Zonation, Regeneration, Lineage Conversion, and Hepatic Malignancy

Hepatocytes are highly specialized epithelial cells that maintain liver metabolic homeostasis, yet they also display remarkable plasticity in response to physiological demands, injury, disease, and oncogenic stress. In this review, we propose hepatocyte plasticity as an integrative framework that links homeostatic metabolic zonation, injury‑ and disease‑induced zonal remodeling and regeneration, hepatobiliary lineage conversion, and zonally biased malignant transformation. We first delineate homeostatic liver zonation as the baseline spatial architecture that constrains, rather than itself constitutes, hepatocyte plasticity, whereas dynamic re-zonation and state conversion represent plastic responses to perturbation. We further propose a conceptual framework that categorizes these plastic responses into four distinct yet interconnected modalities: transient adaptive state transitions, partial lineage conversion, transdifferentiation, and malignant lineage switching. We delineate the multiscale regulatory mechanisms underpinning each category, and critically assess the translational gaps between murine models and human disease. We further explore the therapeutic duality of this plasticity, evaluating emerging approaches that seek either to exploit its regenerative potential for liver repair and disease regression, or to counteract its pathological roles in cancer progression. By integrating these insights, this review establishes a comprehensive framework for understanding hepatocyte plasticity as a central determinant of liver pathobiology and highlights its translational potential for precision therapeutics in liver disease and cancer.