While previous studies have demonstrated that transforming growth factor-β (TGF-β)/SMAD4 signaling modulates epigenetic regulation of specific genes like RUNX1T1 and VAV1, these findings suggest that SMAD4 may also mediate broader epigenetic alterations at the genome level in CCA (Fig. 4). Here, TGFB1 is linked to cholangiocarcinoma.