LAUSR

BACKGROUND & AIMS Liver fibrosis is an intrinsic wound-healing response to chronic injury and the major cause of liver-related morbidity and mortality worldwide. However, no effective diagnostic or therapeutic strategies are available owing to its poorly characterized molecular etiology. Here, we aimed to elucidate the mechanisms underlying liver fibrogenesis. METHODS We performed a quantitative proteomic analysis of clinical fibrotic liver samples to identify dysregulated proteins. Further analyses were performed on the sera of 164 patients with liver fibrosis. Two fibrosis mouse models and several biochemical experiments were used to elucidate liver fibrogenesis. RESULTS We identified cathepsin S upregulation as a central node for extracellular matrix remodeling in the human fibrotic liver by proteomic screening. Increased serum cathepsin S levels efficiently predicted liver fibrosis, even at an early stage. Secreted cathepsin S cleaved collagen 18A1 at its C-terminus, releasing endostatin peptide, which directly bound to and activated hepatic stellate cells via integrin α5β1 signaling, whereas genetic ablation of Ctss remarkably suppressed liver fibrogenesis via endostatin reduction in vivo. Further studies identified macrophages as the main source of hepatic cathepsin S, and splenectomy effectively attenuated macrophage infiltration and cathepsin S expression in the fibrotic liver. Pharmacological inhibition of cathepsin S ameliorated liver fibrosis progression in the mouse models. CONCLUSION Cathepsin S functions as a novel pro-fibrotic factor by remodeling extracellular matrix proteins and may represent a promising target for the diagnosis and treatment of liver fibrosis.