Liver fibrosis is a pathological process primarily driven by activated hepatic stellate cell (HSC). Single-cell transcriptomics of human fibrotic livers identified ASPN (Asporin) as highly expressed in inflammatory and fibrogenic HSC subsets. Clinically, Asporin was markedly elevated in liver tissue and serum, correlating with fibrosis stage across datasets and cohorts, supporting its potential as a non-invasive biomarker. Functionally, Asporin promoted HSC activation and extracellular matrix (ECM) remodeling, whereas its depletion reduced fibrosis in CCl₄-induced mouse models. Mechanistically, Asporin bound directly to ERH and stabilized it by preventing ubiquitin-mediated degradation. Structural modeling showed Asporin masked ERH's K12 ubiquitination site via hydrogen bonds and hydrophobic interactions. ERH overexpression in HSC activated fibrogenic genes and IL-17 signaling, converging on MAPK11 as a common downstream effector. Notably, ERH knockdown abrogated Asporin-driven profibrotic responses. High throughput screening identified prasugrel, a clinically approved drug, as a potent Asporin suppressor. In CCl₄ and high-fat diet induced fibrosis models, prasugrel alleviated fibrosis, inflammation, lipid accumulation, and portal hypertension by suppressing Asporin and ERH expression. Collectively, these findings define the Asporin/ERH/IL-17/MAPK11 axis as a key mediator of HSC activation and fibrogenesis and highlight prasugrel as a promising anti-fibrotic therapy.

Liver fibrosis  /  Hepatic stellate cells  /  Asporin  /  Non-invasive biomarker  /  ERH  /  Extracellular matrix remodeling  /  MAPK11  /  Prasugrel