BDSCs are direct targets of GVHD in a TGF-β-dependent manner. Allo-HCT in mice induces macrophage infiltration into the liver as GVHD develops. Macrophages secrete TGF-β, which induces apoptosis of biliary epithelial cells and reduces the organoid-forming and regenerative capacity of bile duct stem cells. Bile duct stem cell loss results in histological liver damage and reduced liver function. Inhibition of canonical TGF-β signaling with a SMAD2/3 inhibitor preserves bile duct stem cells, restores their organoid-forming capacity, and reduces liver dysfunction. Professional illustration by Somersault18:24.