Abstract

Aim: To investigate the effects and potential mechanisms of thrombospondin 1 (Thbs1) in metabolic dysfunction-associated steatohepatitis (MASH). Methods: Serum Thbs1 concentrations were quantified in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) before and after intervention, and in a biopsy-proven cohort. Moreover, a diet‑induced MASH mouse model was established using a Western diet and fructose water. The involvement of CD47 was evaluated in mice with liver‑specific CD47 overexpression. Further, the immunomodulatory effects of Thbs1 were assessed in lipopolysaccharide-treated RAW264.7 macrophages. Results: Serum Thbs1 levels significantly decreased in patients with MASLD after treatment. Additionally, patients with MASH exhibited higher Thbs1 levels than non-MASH individuals. This elevated Thbs1 level was modestly associated with histopathological severity. Furthermore, short-term Thbs1 administration was associated with reduced hepatic inflammation and early fibrotic features, accompanied by decreased hepatic macrophage infiltration and M1 macrophage-associated signatures in MASH mice. However, liver-specific CD47 overexpression attenuated the observed effects of Thbs1. In vitro, Thbs1 reduced lipopolysaccharide-induced M1 macrophage-associated signatures and pro-inflammatory cytokine expression. Conclusion: Thbs1 suppresses M1 macrophage-associated signatures via CD47 signaling, thereby attenuating liver inflammation and early fibrotic features in MASH mice. These data highlight the Thbs1-CD47 axis as a potential stage‑informed target for MASH treatment.