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.