Extracellular matrix stiffness in chronic liver disease: From mechanisms to treatments

Chronic liver disease (CLD) is a major global health threat and has emerged as a leading cause of human death. CLD essence lies in the remodeling of liver tissue due to excessive accumulation of collagen and extracellular matrix (ECM), which can largely progress to cirrhosis and even lead to end-stage liver diseases. Notably, the progressive elastic forces exerted by the extracellular matrix on cells, known as matrix stiffness, are among the most important mechanical stimuli. Recently, the role of matrix stiffness in the progression of chronic liver disease has been extensively studied. Numerous studies highlighted the increasingly important role of ECM stiffness in the pathogenesis of chronic liver diseases. CLD arises from various causes, such as metabolic disorders, viral infections, excessive alcohol consumption, and cholestatic damage. This study summarises how ECM stiffness regulates cell dysfunction, immune cell polarisation, and ECM synthesis/degradation through multiple mechanosensitive signaling pathways, including integrin-FAK, Hippo-YAP/TAZ, TGF-β-Smad, Piezo1, and Wnt/β-catenin, forming the molecular mechanism of the "increased stiffness-cell activation-ECM deposition" vicious cycle. Importantly, ECM deposition contributes to, but is not equivalent to, ECM stiffness. This review outlines intervention strategies targeting ECM stiffness reduction and related signaling pathways, and discusses the potential applications of ECM stiffness in non-invasive diagnosis and prognosis evaluation. Future research should elucidate the regulatory mechanisms of ECM stiffness, develop multi-target, synergistic therapeutic approaches, and advance its clinical translation for the prevention and treatment of CLD.