In this review, we focus on the balance between the signaling of multiple TGF-β-SF cytokines via Smad-dependent vs. non-Smad pathways and their role in chronic liver conditions, including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC) (Dooley and ten Dijke, 2012; Katz et al., 2016; Dewidar et al., 2019; Rao and Mishra, 2019; Marvin et al., 2020; Nair and Nath, 2020; Gonzalez-Sanchez et al., 2021). The gene discussed is TGFB1; the disease is metabolic dysfunction-associated steatohepatitis.