Taken together, we proposed a regulatory model wherein AMDHD1 inhibited SMAD4 degradation through MH2 domain interaction and concurrently promoted SMAD2/3 phosphorylation, thus activating TGF-β signaling and influencing cell cycle, apoptosis and invasion dynamics in CCA (Fig. 7H). The gene discussed is SMAD2; the disease is cholangiocarcinoma.