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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\u2014including Hippo\u2010YAP, Hedgehog, Notch and TGF\u2010\u03b2\u2014strictly 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\u2010fibrotic niche that perpetuates chronic injury. This review systematically categorizes the disease\u2010specific morphological and molecular subtypes of DR across heterogeneous liver disorders, including metabolic dysfunction\u2010associated 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\u2010cell transcriptomics, lineage tracing and spatial imaging, we comprehensively evaluate widely adopted preclinical models and summarise emerging therapeutic strategies targeting the HPC\u2010DR axis, such as small\u2010molecule compounds, phytochemicals and cytokine modulators. Despite substantial advances in deciphering the HPC\u2010DR axis, critical translational bottlenecks impede its clinical application. Collectively, this review integrates state\u2010of\u2010the\u2010art multidimensional evidence to reconstruct the pathogenic network of HPC\u2010DR interactions, providing mechanistic insights to facilitate precise prognostic evaluation and the development of novel targeted interventions for chronic liver diseases.<\/jats:p>","DOI":"10.1111\/liv.70935","type":"journal-article","created":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T06:20:01Z","timestamp":1792218001000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hepatic Progenitor Cells and the Ductular Reaction: Pathophysiological Role in the Progression of Liver Disease"],"prefix":"10.1111","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2239-7231","authenticated-orcid":false,"given":"Pingping","family":"Wang","sequence":"first","affiliation":[{"name":"Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of 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Medicine (HIM), Chinese Academy of Sciences  Hangzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinan","family":"Lu","sequence":"additional","affiliation":[{"name":"Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences  Hangzhou Zhejiang China"},{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences  Hangzhou Zhejiang China"},{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimin","family":"Su","sequence":"additional","affiliation":[{"name":"Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences  Hangzhou Zhejiang China"},{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songjie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences  Hangzhou Zhejiang China"},{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University  Wenzhou Zhejiang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3073-8746","authenticated-orcid":false,"given":"Yuexing","family":"Tu","sequence":"additional","affiliation":[{"name":"Tongde Hospital of Zhejiang Province Affiliated to Zhejiang Chinese Medical University (Tongde Hospital of Zhejiang Province)  Hangzhou Zhejiang 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