Glucosamine alleviates liver fibrosis through modulation of sinusoidal blood flow and hepatic immune responses

Liver fibrosis, a key precursor to cirrhosis, arises from chronic liver injury and is marked by excessive deposition of extracellular matrix proteins, primarily collagen. This fibrotic remodeling is driven by activation of hepatic stellate cells (HSCs), which are influenced by immune responses from diverse immune cell types, particularly from macrophages. Despite considerable advances in understanding fibrosis pathophysiology, no effective antifibrotic therapies are currently available. Glucosamine (GS), an amino monosaccharide widely used as a dietary supplement for joint health, has demonstrated anti-inflammatory, immunomodulatory, and antifibrotic effects in non-liver contexts, yet its impact on liver fibrosis is unexplored. Here, we show that oral administration of GS significantly ameliorates liver fibrosis by reducing portal hypertension, enhancing hepatic sinusoidal blood flow, and modulating immune responses to inhibit hepatic stellate cell activation. Importantly, GS preserved liver sinusoidal endothelial cell integrity, which is critical for maintaining vascular homeostasis in the fibrotic liver. Moreover, GS suppressed macrophage polarization from the M0 state to pro-inflammatory M1 and pro-fibrotic M2 phenotypes by regulating key metabolic pathways. Our findings suggest a novel application for GS in liver disease, offering a promising and accessible approach to managing fibrosis progression.