An organotypic model of ductular reaction reveals a mevalonate-dependent vulnerability in reactive biliary cells

  • Cell Rep. 2025 Dec 23;44(12):116681. doi: 10.1016/j.celrep.2025.116681.
Beatrice Anfuso  1 ,  Suresh Velnati  1 ,  Davide Selvestrel  1 ,  Clara Garlant  2 ,  Elisa Ferracci  3 ,  Gabriele Baj  4 ,  Pietro Parisse  5 ,  Diletta Overi  6 ,  Rebecca Bertolio  1 ,  Roberta Bulla  4 ,  Aurelio Sonzogni  7 ,  Matteo Bramuzzo  8 ,  Loredana Casalis  9 ,  Nicholas Cocomello  10 ,  Francesco Baratta  10 ,  Maria Del Ben  10 ,  Pablo Giraudi  11 ,  Claudio Tiribelli  11 ,  Natalia Rosso  11 ,  Manuela Mastronardi  12 ,  Paola Tarchi  13 ,  Maurizio Pinamonti  14 ,  Fabrizio Zanconati  15 ,  Nicolò de Manzini  12 ,  Eugenio Gaudio  6 ,  Silvia Palmisano  12 ,  Deborah Bonazza  15 ,  Giannino Del Sal  16 ,  Guido Carpino  6 ,  Fulvio Chiacchiera  3 ,  Giovanni Sorrentino  17
Affiliations
  • 1. International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park - Padriciano, 34149 Trieste, Italy.
  • 2. International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park - Padriciano, 34149 Trieste, Italy; Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste.
  • 3. Laboratory of Stem Cells and Cancer Genomics, Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy.
  • 4. Department of Life Sciences, University of Trieste, Trieste, Italy.
  • 5. Elettra-Sincrotrone Trieste, Area Science Park Basovizza, 34149 Trieste, Italy; Institute of Materials (IOM), Italian National Research Council (CNR), Area Science Park Basovizza, 34149 Trieste, Italy.
  • 6. Department of Anatomical, Histological, Forensic Medicine and Orthopaedic Sciences, Sapienza University of Rome, Roma, Italy.
  • 7. Department of Pathology, Policlinico di Monza, Monza, Italy.
  • 8. Institute for Maternal and Child Health - IRCCS "Burlo Garofolo," Trieste, Italy.
  • 9. Elettra-Sincrotrone Trieste, Area Science Park Basovizza, 34149 Trieste, Italy.
  • 10. Department of Clinical Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.
  • 11. Fondazione Italiana Fegato, Area Science Park Basovizza, Trieste, Italy.
  • 12. Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste; Surgical Clinic Unit, Cattinara Hospital, ASUGI, Strada di Fiume, 447, 34149 Trieste, Italy.
  • 13. Surgical Clinic Unit, Cattinara Hospital, ASUGI, Strada di Fiume, 447, 34149 Trieste, Italy.
  • 14. Department of Pathology, University Hospital Cattinara, Trieste, Italy.
  • 15. Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste.
  • 16. International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park - Padriciano, 34149 Trieste, Italy; Department of Life Sciences, University of Trieste, Trieste, Italy; IFOM ETS, The AIRC Institute of Molecular Oncology, Milan, Italy.
  • 17. International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park - Padriciano, 34149 Trieste, Italy; Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste. Electronic address: [email protected].
PMID: 41389211 DOI: 10.1016/j.celrep.2025.116681
Abstract

Chronic liver injury is marked by the emergence of ductular reaction (DR), where reactive biliary epithelial cells (BECs) proliferate and engage in multicellular networks, driving disease progression. Despite its clinical relevance, the mechanisms underlying DR activation remain elusive, partly due to the lack of physiologically relevant models. Here, we developed an organotypic ex vivo model of DR using precision-cut liver slices (PCLS) from mouse and human tissue, which preserves native architecture and enables de novo activation of BECs. Through integrated analysis of PCLS and patient-derived organoids, we identified the mevalonate (MVA) pathway as a metabolic dependency of DR. Mechanistically, accumulation of Cholesterol and geranylgeranyl-pyrophosphate is required to sustain a reactive BEC phenotype. Importantly, MVA pathway activation was confirmed in patient biopsies, and statin use suppressed DR both ex vivo and in clinical cohorts. These findings establish an innovative translational platform and reveal an actionable metabolic vulnerability in human DR cells.

Keywords
CP: Metabolism; CP: Stem cell research; YAP; cholangiocytes; cholesterol metabolism; chronic liver disease; hepatic progenitor cells; liver regeneration; mevalonate pathway; organoids; precision-cut liver slices; statins.
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