An organotypic model of ductular reaction reveals a mevalonate-dependent vulnerability in reactive biliary cells
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.
Authors
- Paola Tarchi (ORCID: https://orcid.org/0000-0002-7139-3951)
- Nicolò de Manzini (ORCID: https://orcid.org/0000-0002-8362-9044)
- Beatrice Anfuso (ORCID: https://orcid.org/0000-0001-7819-6830)
- Francesco Baratta (ORCID: https://orcid.org/0000-0003-1708-272X)
- Aurelio Sonzogni (ORCID: https://orcid.org/0000-0001-5001-9533)
- Maurizio Pinamonti (ORCID: https://orcid.org/0000-0002-9277-9378)
- Matteo Bramuzzo (ORCID: https://orcid.org/0000-0002-5249-8248)
- Elisa Ferracci (ORCID: https://orcid.org/0000-0003-2515-0518)
- Deborah Bonazza (ORCID: https://orcid.org/0000-0002-5605-6711)
- Maria Del Ben (ORCID: https://orcid.org/0000-0003-1199-8454)
- Suresh Velnati (ORCID: https://orcid.org/0000-0002-6756-9854)
- Fabrizio Zanconati (ORCID: https://orcid.org/0000-0001-5357-9579)
- Guido Carpino (ORCID: https://orcid.org/0000-0001-8570-2519)
- Rebecca Bertolio (ORCID: https://orcid.org/0000-0001-5451-7820)
- Nicholas Cocomello (ORCID: https://orcid.org/0000-0002-4922-4318)
- Diletta Overi (ORCID: https://orcid.org/0000-0003-3561-8903)
- Silvia Palmisano (ORCID: https://orcid.org/0000-0003-4749-4258)
- Fulvio Chiacchiera (ORCID: https://orcid.org/0000-0003-3830-2090)
- Manuela Mastronardi (ORCID: https://orcid.org/0000-0003-3525-3692)
- Davide Selvestrel
- Gabriele Baj (ORCID: https://orcid.org/0000-0002-2625-9454)
- Giannino Del Sal (ORCID: https://orcid.org/0000-0003-2185-6003)
- Loredana Casalis (ORCID: https://orcid.org/0000-0001-8924-4906)
- Giovanni Sorrentino (ORCID: https://orcid.org/0000-0001-8628-8778)
- Eugenio Gaudio (ORCID: https://orcid.org/0000-0001-8441-6625)
- Claudio Tiribelli (ORCID: https://orcid.org/0000-0001-6596-7595)
- Pietro Parisse (ORCID: https://orcid.org/0000-0002-7420-2778)
- Natalia Rosso (ORCID: https://orcid.org/0000-0002-4251-3547)
- Pablo José Giraudi (ORCID: https://orcid.org/0000-0003-2852-6648)
- Roberta Bulla (ORCID: https://orcid.org/0000-0003-1737-5776)
- Clara Garlant
Institutions
- University of Trieste (IT)
- University of Trento (IT)
- IRCCS Materno Infantile Burlo Garofolo (IT)
- AREA Science Park (IT)
- Elettra-Sincrotrone Trieste S.C.p.A. (IT)
- Fondazione Italiana Fegato (IT)
- Ospedale di Cattinara (IT)
- Fondazione Lanza (IT)
- Sapienza University of Rome (IT)
- International Centre for Genetic Engineering and Biotechnology (IT)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.116681
- Primary Topic
- Liver physiology and pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00