Lumican–TLR4 interaction accelerates hepatic fibrosis by activating hepatic stellate cells

BACKGROUND: Lumican expression is associated with liver fibrosis across various etiologies. However, its precise role and underlying mechanisms in liver fibrosis remain unclear. METHODS: Lumican knockout (Lum KO) mice were generated, and liver fibrosis was induced using bile duct ligation (BDL) and carbon tetrachloride (CCl4) to investigate the in vivo role of Lumican. Proteomic analyses and target validation were performed to elucidate the mechanisms by which Lumican contributes to liver fibrosis. RESULTS: Lumican is predominantly expressed in hepatic stellate cells (HSCs) and promotes their activation. Lumican deficiency attenuates liver fibrosis progression in mice following BDL and CCl4 administration. Proteomic analysis identified Lumican as a ligand of toll-like receptor 4 (TLR4). Lumican directly binds to TLR4, activating downstream SMAD3-mediated pro-fibrotic signaling pathways, thereby promoting HSC activation and contributing to liver fibrosis development. CONCLUSIONS: Lumican plays a critical role in HSC activation and liver fibrosis progression via the Lumican-TLR4-SMAD3 axis, highlighting it as a potential therapeutic target for anti-fibrotic intervention.