CD209a regulates metabolic dysfunction-associated steatotic liver disease development through macrophage STAT3 signaling pathway.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health concern, with macrophage-driven inflammation playing a critical role in its progression. CD209a, a C-type lectin receptor, has been implicated in immune regulation, but its function in MASLD remains unclear. This study investigates the role of CD209a in MASLD pathogenesis, focusing on its effects on macrophage-mediated inflammation. METHODS: We analyzed CD209a expression in liver tissues from patients with MASLD and diet-induced MASLD mouse models. CD209a knockout (Cd209a(−/−)) mice were generated, and bone marrow transplantation was conducted to assess the impact of CD209a deficiency on hepatic steatosis, inflammation, and insulin resistance. Macrophage depletion was performed to determine whether the impact is mediated by liver macrophages. Single-cell RNA sequencing (scRNA-seq) was utilized to explore macrophage phenotypic changes and underlying signaling pathways. RESULTS: CD209a expression was significantly upregulated in livers of patients and mice with MASLD. Cd209a(−/−) mice exhibited aggravated hepatic steatosis, inflammation, and insulin resistance compared with wild-type controls (P < 0.05). Macrophage depletion abolished these effects, confirming a macrophage-dependent mechanism. Single-cell RNA-seq revealed that CD209a deficiency caused a shift toward a proinflammatory macrophage phenotype, with STAT3 signaling identified as a potential mediator. CONCLUSIONS: CD209a plays a protective role in MASLD. Loss of CD209a promotes macrophage-driven inflammation through STAT3 signaling and exacerbates MASLD severity. CD209a may serve as a potential therapeutic target for MASLD management, warranting further translational research. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s11658-025-00824-5.