ADAMTS4 elicits myeloid-derived immune cell recruitment and liver fibrogenesis in metabolic dysfunction-associated steatotic liver disease.

A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) has been implicated in arthritis and lung fibroblast activation; however, its role in liver homeostasis and fibrogenesis remains largely unexplored. Here, we investigated the functional significance of ADAMTS4 in liver fibrosis. We found that hepatic ADAMTS4 mRNA expression was significantly elevated in patients with fibrotic steatohepatitis. In mouse models of liver fibrosis, genetic deletion of ADAMTS4 protected against liver fibrogenesis, accompanied by a marked reduction in the recruitment of myeloid-derived infiltrating macrophages. Mechanistically, ADAMTS4-mediated cleavage of versican generated versikine, which promoted macrophage migration and differentiation toward a pro-inflammatory phenotype in vitro. In addition, tumor necrosis factor (TNF)α significantly increased both the mRNA expression and protein secretion of ADAMTS4. Furthermore, ADAMTS4 directly induced collagen accumulation through activation of signal transducer and activator of transcription 3 (STAT3) in LX2 cells. To explore the potential genetic regulation of ADAMTS4 expression, we performed response-eQTL analysis in patients with metabolic dysfunction-associated steatotic liver disease and identified a single-nucleotide polymorphism associated with increased ADAMTS4 expression in a subset of patients carrying a specific genotype. Collectively, our findings identify ADAMTS4 as a critical regulatory factor that promotes the recruitment of myeloid-derived infiltrating macrophages and collagen accumulation during liver fibrogenesis, suggesting that targeting ADAMTS4 may represent a potential therapeutic strategy for liver fibrosis.