Angelica sinensis polysaccharides modulate iron metabolism and macrophage polarization to alleviate rheumatoid arthritis.

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and systemic complications. Recent evidence has indicated that disrupted iron metabolism, notably elevated hepcidin expression and excessive iron accumulation in tissues, contributes to RA progression. In RA, Macrophages, which play a central role in both immune regulation and iron homeostasis, are often polarized toward the proinflammatory M1 phenotype. In this study, we investigated the therapeutic effects of Angelica sinensis polysaccharides (ASP, 100-400 mg/kg) in a collagen-induced arthritis (CIA) mouse model. ASP significantly alleviated joint swelling, histopathological damage, and iron deposition in the liver and spleen. It also downregulated hepcidin expression and restored the M1/M2 macrophage balance. Furthermore, immunofluorescence and western blotting confirmed increased ferroportin (FPN) and decreased ferritin levels in splenic macrophages. In an in vitro coculture model mimicking inflammation, ASP indirectly modulated macrophage iron handling and polarization by suppressing hepatocyte-derived hepcidin. RNA-seq analysis revealed that ASP treatment downregulated HIF-1α and NF-κB pathways, which link iron metabolism to macrophage activation, whereas the results of reactive oxygen species (ROS) assays supported its role in reducing oxidative stress associated with iron overload. Together, these findings suggest that ASP alleviates RA symptoms by restoring iron homeostasis and modulating macrophage polarization, primarily by targeting the hepcidin-FPN axis and related inflammatory pathways. ASP therefore holds promise as a low-toxicity, immunomodulatory candidate for RA therapy.