Hepatic Progenitor Cells and the Ductular Reaction: Pathophysiological Role in the Progression of Liver Disease

Ductular reaction (DR), a defining histological hallmark of diverse acute and chronic liver injuries, is fundamentally driven by the activation of hepatic progenitor cells (HPCs) and their complex, spatiotemporal bidirectional crosstalk within the hepatic niche. As bipotent precursor cells, HPCs initiate compensatory regeneration when mature hepatocyte proliferation is compromised. However, DR is not a uniform process but a multiphase dynamic reaction: transient early activation facilitates parenchymal restoration, whereas persistent, dysregulated HPC expansion fuels progressive fibrogenesis. The convergence of conserved developmental signalling cascades-including Hippo-YAP, Hedgehog, Notch and TGF-β-strictly governs HPC fate commitment and biliary epithelial proliferation. Concurrently, DR orchestrates intricate inflammatory circuitries by recruiting innate and adaptive immune cells, activating hepatic stellate cells and remodelling the extracellular matrix, thereby establishing a pro-fibrotic niche that perpetuates chronic injury. This review systematically categorizes the disease-specific morphological and molecular subtypes of DR across heterogeneous liver disorders, including metabolic dysfunction-associated steatotic liver disease (MASLD), viral hepatitis and cholestatic liver diseases, highlighting its robust value as an independent histological and serological prognostic biomarker. Leveraging recent mechanistic breakthroughs from single-cell transcriptomics, lineage tracing and spatial imaging, we comprehensively evaluate widely adopted preclinical models and summarise emerging therapeutic strategies targeting the HPC-DR axis, such as small-molecule compounds, phytochemicals and cytokine modulators. Despite substantial advances in deciphering the HPC-DR axis, critical translational bottlenecks impede its clinical application. Collectively, this review integrates state-of-the-art multidimensional evidence to reconstruct the pathogenic network of HPC-DR interactions, providing mechanistic insights to facilitate precise prognostic evaluation and the development of novel targeted interventions for chronic liver diseases.