Matrix Mechanics as Regulatory Factors and Therapeutic Targets in Hepatic Fibrosis

The hallmark of liver fibrosis is excessive extracellular matrix (ECM) synthesis and deposition that improve liver matrix remodeling and stiffening. Increased matrix stiffness is not only a pathological consequence of liver fibrosis in traditional view, but also recognized as a key driver in pathological progression of hepatic fibrosis. Cells can perceive changes in the mechanical characteristics of hepatic matrix and respond by means of mechanical signal transduction pathways to regulate cell behavior. In this review, the authors first classify causes of liver matrix stiffening during fibrotic progression, such as higher degree of collagen cross-linking. The latest advances of the research on the matrix mechanics in regulating activation of HSCs or fibroblasts under two-dimensional (2D) and three-dimensional (3D) microenvironment is also classified and summarized. The mechanical signaling pathways involved in the process of hepatic matrix stiffening, such as YAP-TAZ signaling pathway, are further summarized. Finally, some potential therapeutic concepts and strategies based on matrix mechanics will be detailed. Collectively, these findings reinforce the importance of matrix mechanics in hepatic fibrosis, and underscore the value of clarifying its modulation in hopes of advancing the development of novel therapeutic targets and strategies for hepatic fibrosis.