An organotypic model of ductular reaction reveals a mevalonate-dependent vulnerability in reactive biliary cells
Year: 2025
Type: article
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.
Source: Cell Reports
Authors: Beatrice Anfuso, Suresh Velnati, Davide Selvestrel, Clara Garlant, Elisa Ferracci, Gabriele Baj, Pietro Parisse, Diletta Overi, Rebecca Bertolio, Roberta Bulla, Aurelio Sonzogni, Matteo Bramuzzo, Loredana Casalis, Nicholas Cocomello, Francesco Baratta, Maria Del Ben, Pablo Giraudi, Claudio Tiribelli, Natalia Rosso, Manuela Mastronardi, Paola Tarchi, Maurizio Pinamonti, Fabrizio Zanconati, Nicolò de Manzini, Eugenio Gaudio, Silvia Palmisano, Deborah Bonazza, Giannino Del Sal, Guido Carpino, Fulvio Chiacchiera, Giovanni Sorrentino
Institutions: International Centre for Genetic Engineering and Biotechnology, University of Trieste, AREA Science Park, University of Trento, Elettra-Sincrotrone Trieste S.C.p.A., Istituto Officina dei Materiali, National Research Council, Sapienza University of Rome, IRCCS Materno Infantile Burlo Garofolo, Fondazione Italiana Fegato, Ospedale di Cattinara, IFOM
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
OpenAlex ID: W4417259043