SMAD4 and hepatocellular carcinoma: Of note, similar to the dichotomous effects of TGF-β-SF ligands in HCC (Table 3), Smad4 displays a dichotomous behavior; while positively associated with tumor suppression at the initial stages of HCC, it becomes a tumor promoter at the late stages (Hernanda et al., 2015; Xin et al., 2024).