Hyaluronic Acid in Liver Fibrosis: Role in Inflammation, Tissue Remodeling, and Disease Progression

Hyaluronic acid (HA) is a major glycosaminoglycan in the hepatic extracellular matrix and pericellular space, playing a critical role in maintaining liver architecture and regulating cell-matrix interactions. In chronic liver disease, particularly in metabolic dysfunction-associated steatotic liver disease (MASLD), aberrant HA metabolism, especially the accumulation of low-molecular-weight HA, contributes to fibrogenesis, immune dysregulation, and hepatocellular carcinoma development through receptor-mediated pathways involving CD44, RHAMM, and Toll-like receptors. This review synthesizes current evidence on HA biosynthesis, turnover, and signaling, emphasizing its dual role as a structural scaffold and as an active modulator of immune responses and tumor progression in chronic liver disease. We place special emphasis on its immunomodulatory function during the progression from MASLD to HCC and discuss its emerging relevance as therapeutic target. Potential strategies to counteract HA-mediated pathology, including inhibition of HA synthesis, enzymatic degradation, and receptor blockade, are also critically examined.