4EBP1 phosphorylation mediates TGF-β1-induced hepatic fibrosis and upregulates HIF-1α expression.

Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation (p-4EBP1) has been involved in the production of excess extracellular matrix (ECM) and the fibrosis of various organs. We first confirmed that the p-4EBP1 and HIF-1α expressions were significantly elevated in transforming growth factor β1 (TGF-β1)-activated LX-2 cells and fibrotic liver samples. In vivo experiments supported the antifibrotic effect of targeting p-4EBP1 in the liver. Genetic or drug-targeted p-4EBP1 activity in vitro decreased TGF-β1-induced activation, proliferation, migration, epithelial-mesenchymal transition (EMT), and the HIF-1α protein expression in LX-2 cells and promoted their apoptosis. Moreover, the short hairpin RNA-mediated knockdown of 4EBP1 was the opposite. In conclusion, our findings suggest that p-4EBP1 is a critical signaling node in TGF-β1-induced hepatic fibrosis and identified what we believe to be a previously unrecognized p-4EBP1/HIF-1α signaling for hepatic stellate cell (HSC) fibrosis transformation.