The Matrix Reloaded: The Hepatic Matrisome as a Therapeutic Opportunity to Fight Liver Fibrosis

Liver fibrosis is the excessive accumulation of extracellular matrix (ECM) that occurs in most types of chronic liver diseases (CLDs) as a response to sustained liver injury. While the ECM comprises different proteins, collagen being the most abundant, the term matrisome refers to a plethora of ECM-related molecules, including collagen-associated proteins, growth factors, cytokines, enzymes and their endogenous inhibitors. The hepatic matrisome undergoes significant qualitative and quantitative changes during liver fibrosis. Despite intense research over recent years, our understanding of the matrisome in the liver-both in health and disease-and particularly of its function beyond its conventional structural role, remains poor. This review highlights how comprehending hepatic matrisome responses to liver injury can yield novel insights into disease progression and regression and could be exploited as a potential antifibrotic strategy. The antifibrotic potency of drugs that interfere with the matrisome at different levels has been demonstrated in preclinical studies, but translation to clinical trials remains still limited. So far, simtuzumab (LOXL2 inhibitor antibody), imatinib (small-molecule inhibitor against discoidin domain receptors-DDRs), bexotegrast (integrin inhibitor), GR-MD-02 (galectin 3 inhibitor), and BMS-986263 (siRNA-targeting HSP47) have been or are being evaluated in clinical trials related to CLD, and some of them have shown promising results.