Fig. 5

TGF-β and Wnt/β-catenin canonical signaling in liver diseases. Upon liver injury, TGF-β secreted from other liver cell types binds to its receptor TGF-βRII, which subsequently recruits TGF-βRI to synergistically mediate downstream pathways: canonical SMAD-dependent pathway and non-SMAD pathways. In canonical pathway, the SMAD oligomers translocate into the nucleus, where they function as transcription factors, mediating the transcriptional activation. In non-SMAD pathway, PI3K/Akt and MAPK pathways are activated by TGF-βRs. These pathways induce expression of genes, such as α-SMA, Collagens, fibronectin, TIMP-1, LOXL-1, and Kindlin-2, leading to HSC activation, ECM production and stabilization, and cell adhesion. These processes collectively promote liver fibrosis. In a healthy liver, Wnt signaling is typically inactive due to the absence of Wnt-Wnt receptor interactions and the degradation of β-catenin by a protein complex, which includes axis inhibition protein (AXIN), adenomatous polyposis coli (APC), and E3 ubiquitin ligase. During liver oncogenic injury, Wnt proteins bind to Fzd receptor and LRP-5/6 co-receptors, activating the canonical pathway. This activation causes degradation complex to translocate to the cell membrane, preventing the degradation of β-catenin. The β-catenin then enters the nucleus, where it binds with TCF/LEF transcription factors to regulate target gene expression, such as c-Myc, cyclin-D1 and pyruvate kinase M2 (PKM-2). These genes are involved in promoting tumor cell metabolism, proliferation, migration, and metastasis in HCC and ICC. This figure was generated with Adobe Illustrator