ArticleJournal of hepatology2023
Hepatocyte dedifferentiation profiling in alcohol-related liver disease identifies CXCR4 as a driver of cell reprogramming.
Article in Journal of hepatology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 28 citations in OpenAlex.
- Clinicopathological features of hepatobiliary cells in primary biliary cholangitis patients with incomplete response to ursodeoxycholic acid.BMC gastroenterology · 2026Article
- Cholestasis in Alcohol-Associated Liver Disease.The American journal of pathology · 2026Review
- Zonation, Zonation, Zonation: The Real Estate of the Liver.Annual review of pathology · 2026Review
- Multi-omics analysis identifies a hepatocyte-associated signature in alcohol-related liver injury.Frontiers in immunology · 2026Article
- Derepression of the epithelial transcription factor GRHL2 promotes direct hepatocyte-to-cholangiocyte transdifferentiation.PLoS biology · 2025Article
- [Bioinformatics screening and analysis of key genes of ferroptosis and autophagy in alcoholic liver disease and their validation].Zhonghua gan zang bing za zhi = Zhonghua ganzangbing zazhi = Chinese journal of hepatology · 2025Article
- Therapeutic targeting of myeloid cells in liver fibrosis: Mechanisms and clinical prospects.Animal models and experimental medicine · 2025Review
- Changes in the FXR-cistrome and alterations in bile acid physiology in Wilson disease.Hepatology communications · 2025Article
- Portal Fibrosis and the Ductular Reaction: Pathophysiological Role in the Progression of Liver Disease and Translational Opportunities.Gastroenterology · 2025Review
- Single-cell landscape of the intrahepatic ecosystem in alcohol-related liver disease.Clinical and translational medicine · 2025Article
- Albiflorin inhibits inflammation to improve liver fibrosis by targeting the CXCL12/CXCR4 axis in mice.Frontiers in pharmacology · 2025Article
- Immunology and treatments of fatty liver disease.Archives of toxicology · 2025Review
- Stromal Cell Derived Factor-1 Promotes Hepatic Insulin Resistance via Inhibiting Hepatocyte Lipophagy.Journal of cellular and molecular medicine · 2025Article
- YAP mediates HIV-related liver fibrosis.JHEP reports : innovation in hepatology · 2024Article
- Pathogenesis of Alcohol-Associated Liver Disease.Clinics in liver disease · 2024Review
- Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease.eGastroenterology · 2024Article
- Review
- Unraveling the complexities of fibrosis and ductular reaction in liver disease: pathogenesis, mechanisms, and therapeutic insights.American journal of physiology. Cell physiology · 2024Review
- Alcohol-associated liver disease.The Journal of clinical investigation · 2024Review
- Human Precision-Cut Liver Slices: A Potential Platform to Study Alcohol-Related Liver Disease.International journal of molecular sciences · 2023Article
Corrections and comments
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Authors and funding
24 authors at 6 institutions in 3 countries.
Funding
Abstract
BACKGROUND &
aimsLoss of hepatocyte identity is associated with impaired liver function in alcohol-related hepatitis (AH). In this context, hepatocyte dedifferentiation gives rise to cells with a hepatobiliary (HB) phenotype expressing biliary and hepatocyte markers and showing immature features. However, the mechanisms and impact of hepatocyte dedifferentiation in liver disease are poorly understood.
methodsHB cells and ductular reaction (DR) cells were quantified and microdissected from liver biopsies from patients with alcohol-related liver disease (ArLD). Hepatocyte-specific overexpression or deletion of C-X-C motif chemokine receptor 4 (CXCR4), and CXCR4 pharmacological inhibition were assessed in mouse liver injury. Patient-derived and mouse organoids were generated to assess plasticity.
resultsHere, we show that HB and DR cells are increased in patients with decompensated cirrhosis and AH, but only HB cells correlate with poor liver function and patients' outcome. Transcriptomic profiling of HB cells revealed the expression of biliary-specific genes and a mild reduction of hepatocyte metabolism. Functional analysis identified pathways involved in hepatocyte reprogramming, inflammation, stemness, and cancer gene programs. The CXCR4 pathway was highly enriched in HB cells and correlated with disease severity and hepatocyte dedifferentiation. In vitro, CXCR4 was associated with a biliary phenotype and loss of hepatocyte features. Liver overexpression of CXCR4 in chronic liver injury decreased the hepatocyte-specific gene expression profile and promoted liver injury. CXCR4 deletion or its pharmacological inhibition ameliorated hepatocyte dedifferentiation and reduced DR and fibrosis progression.
conclusionsThis study shows the association of hepatocyte dedifferentiation with disease progression and poor outcome in AH. Moreover, the transcriptomic profiling of HB cells revealed CXCR4 as a new driver of hepatocyte-to-biliary reprogramming and as a potential therapeutic target to halt hepatocyte dedifferentiation in AH. IMPACT AND IMPLICATIONS: Here, we show that hepatocyte dedifferentiation is associated with disease severity and a reduced synthetic capacity of the liver. Moreover, we identify the CXCR4 pathway as a driver of hepatocyte dedifferentiation and as a therapeutic target in alcohol-related hepatitis. Therefore, this study reveals the importance of preserving strict control over hepatocyte plasticity in order to preserve liver function and promote tissue repair.
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