Figure 3.

TM4SF5-mediated liver disease development. Healthy livers can be injured by different stimuli, including excessive nutrients, leading to lipid toxicity and hepatocyte damage. Following chronic damage, components of the inflammatory environment, including TGFβ1, CCL, CCL5, etc., can induce TM4SF5 expression in hepatocytes. Enhanced TM4SF5 can play roles in the regulation of the immunometabolic pathway and activity, consequently leading to the development of nonalcoholic steatosis (NAFL) with increased lipid uptake and accumulation, nonalcoholic steatohepatitis (NASH) with further inflammation and immune cell infiltration, fibrosis with STAT3-mediated extracellular matrix (i.e., collagen type I, laminin γ2, etc.) deposition, and eventually, hepatocellular carcinoma (HCC) with increased expression levels of AFP (α-fetoprotein), FUCA (α-L-Fucosidase 1), CD34 (CD34 antigen), laminin γ2, etc. TM4SF5-positive HCC can have features of the epithelial–mesenchymal transition (EMT) and actin reorganization, increasing the metastatic potential through the promotion of migration and invasion. Each dotted arrow indicates TM4SF5-mediated effects on the pathological development or progression. SOCS1/3, suppressor of cytokine signaling 1/3; STAT3, signal transducer and activator of transcription 3; SIRT1, Sirtuin 1; SREBPs, sterol regulatory element binding proteins; CCL2/5, C-C motif chemokine ligand 2/5; TGFβ1, transforming growth factor β1.