Macrophage-derived S100A9 drives liver fibrosis in Echinococcus multilocularis infection by up-regulating secreted protein acidic and rich in cysteine (SPARC) in hepatic stellate cells.

Alveolar echinococcosis (AE), caused by Echinococcus multilocularis(E. multilocularis) infection, is a severe parasitic disease characterized by progressive liver fibrosis. Although the damage-associated molecular pattern molecule S100A9 has been implicated in some inflammatory and fibrotic diseases, its role in AE induced liver fibrosis remains unclear. This study aimed to elucidate the function and mechanism of S100A9 in E. multilocularis induced liver fibrogenesis. Using proteomic analysis, we identified significant up-regulation of S100A9 in the livers of infected mice. In a stem cell-based fibrosis regression model, S100A9 expression correlated closely with the extent of fibrosis. Cellular localization and macrophage depletion experiments revealed macrophages as the primary source of S100A9. In vitro, recombinant S100A9 directly activated human hepatic stellate cells (HSCs) LX-2, up-regulating fibrotic markers in a time-dependent manner. Proteomic and molecular analyses further identified SPARC as a critical downstream mediator, and SPARC knockdown attenuated S100A9 induced HSCs activation and TGF-β/SMAD signaling. In vivo, pharmacological inhibition of S100A9 with tasquinimod significantly ameliorated liver fibrosis, down-regulated SPARC expression, and suppressed SMAD2/3 phosphorylation. Critically, histopathological analysis of liver tissues from AE patients confirmed that S100A9 expression was predominantly localized to fibrotic areas and positively correlated with fibrosis severity. Collectively, these results demonstrate that macrophage-derived S100A9 promotes HSCs activation and liver fibrosis via SPARC dependent way, mechanism, and its clinical relevance in human AE substantiates the S100A9-SPARC axis as a potential therapeutic target in AE.