Ductular reaction as a spatial fibrogenic niche: cholangiocyte–macrophage–fibroblast crosstalk in chronic liver disease

Ductular reaction—the expansion of reactive bile ductules at the portal–parenchymal interface—has traditionally been interpreted as a proliferative or regenerative response of the biliary epithelium to chronic injury. Here we argue that this histological phenomenon is better understood as a spatial fibrogenic niche: a physically organized, self-reinforcing microenvironment in which reactive cholangiocytes, macrophages, and matrix-producing mesenchymal cells engage in bidirectional signaling that converts repair into fibrosis. We integrate single-cell and spatial transcriptomic evidence showing that reactive cholangiocytes act as a signaling hub, secreting TGF-β, PDGF, CCL2, CXCL chemokines, IL-6, osteopontin, and Hedgehog ligands; that recruited and tissue-resident macrophages amplify this axis; and that portal fibroblasts and hepatic stellate cells close a feed-forward loop by depositing extracellular matrix and growth factors that sustain the niche. We propose that a cholangiocyte–macrophage–fibroblast feed-forward loop, stabilized by chemokine-driven recruitment, TGF-β-centered fibrogenesis, mechanical feedback, and senescence, underlies ductular-associated fibrosis across cholestatic and metabolic liver diseases. Targeting the pathological organization of this niche—rather than any single cell type—may offer a new therapeutic framework for chronic liver fibrosis.