Hepatic stellate cell-derived thrombospondin-2 as a novel therapeutic target for liver fibrosis regardless of etiology

Thrombospondin-2 (THBS2) expression is closely associated with liver fibrosis regardless of etiology. However, the role of THBS2 in the pathogenesis of liver fibrosis has not been elucidated yet. Here we report THBS2 is predominantly expressed in activated HSCs and dynamically increases with liver fibrosis progression and decreased in regression. Selective interference of HSC Thbs2 evidently retards fibrosis progression and intrahepatic inflammatory infiltration in liver fibrosis mouse models. Mechanically, extracellular THBS2, as a dimer, specifically recognizes and directly binds to TLR4 receptor, activating HSCs via stimulating downstream profibrotic focal adhesion kinase (FAK)/transforming growth factor beta (TGF-β) pathways. Disruption of THBS2-TLR4-FAK/TGF-β signaling axis notably alleviates HSC activation and liver fibrosis aggravation. In conclusion, THBS2 plays a crucial role in HSC activation and liver fibrosis progression through TLR4-FAK/TGF-β signaling in an autocrine manner. Therapies targeting HSC Thbs2 via AAV6 vector-capsulated shRNA may represent a novel promising strategy to prevent or treat liver fibrosis.