Abstract
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, regardless of etiology, dysregulated HA metabolism, particularly the generation and accumulation of low-molecular-weight HA (LMW-HA), has been implicated in fibrogenesis, immune dysregulation, and hepatocellular carcinogenesis via receptor-mediated pathways involving lymphocyte homing receptor (CD44), receptor for hyaluronan-mediated motility (RHAMM), and Toll-like receptors (TLRs). 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. Given the rising global burden of metabolic liver disease, and in line with our recent findings that small HA fragments are elevated in obesity and promote low-grade, TLR-dependent activation of innate immune cells, we emphasize metabolic dysfunction-associated steatotic liver disease (MASLD) as a highly prevalent and clinically relevant setting to examine HA-driven immunomodulation during progression to advanced fibrosis and hepatocellular carcinoma (HCC) and to consider therapeutic strategies targeting HA synthesis, turnover, or receptor signaling.