Dual Signaling Pathways of TGF-β Superfamily Cytokines in Hepatocytes: Balancing Liver Homeostasis and Disease Progression

Yoav I. Henis ^1* Roohi Chaudhary ^1,2 Ralf Weiskirchen ³ Marcelo Ehrlich ^2*

• ¹ Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
• ² The Shmunis School of Biomedicine and Cancer Research, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Tel Aviv, Israel
• ³ Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and Clinical Chemistry, University Hospital RWTH Aachen, Aachen, Germany

The transforming growth factor-β (TGF-β) superfamily (TGF-β-SF) comprises over 30 cytokines, including TGF-β, activins/inhibins, bone morphogenetic proteins (BMPs), and growth differentiation factors (GDFs). These cytokines play critical roles in liver function and disease progression. Here, we discuss Smad-dependent (canonical) and non-Smad pathways activated by these cytokines in a hepatocellular context. We highlight the connection between the deregulation of these pathways or the balance between them and key hepatocellular processes (e.g., proliferation, apoptosis, and epithelialmesenchymal transition (EMT)). We further discuss their contribution to various chronic liver conditions, such as metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and hepatocellular carcinoma (HCC). In MASLD and MASH, TGF-β signaling contributes to hepatocyte lipid accumulation, cell death and fibrosis progression through both Smad and non-Smad pathways. In HCC, TGF-β and other TGF-β-SF cytokines have a dual role, acting as tumor suppressors or promoters in early vs. advanced stages of tumor progression, respectively. Additionally, we review the involvement of non-Smad pathways in modulating hepatocyte responses to TGF-β-SF cytokines, particularly in the context of chronic liver diseases, as well as the interdependence with other key pathways (cholesterol metabolism, insulin resistance, oxidative stress and lipotoxicity) in MASLD/MASH pathogenesis. The perspectives and insights detailed in this review may assist in determining future research directions and therapeutic targets in liver conditions, including chronic liver diseases and cancer. are critical for multiple physiological and pathological processes, including several types of cancer, fibrosis, apoptosis, skeletal and vascular diseases, primary pulmonary hypertension, and angioproliferative disorders (