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 (CCl 4 ) 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 CCl 4 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.