Ferroportin inhibits the proliferation and migration of fibroblast-like synoviocytes in rheumatoid arthritis via regulating ROS/PI3K/AKT signaling pathway.

The aberrant proliferation of fibroblast-like synoviocytes (FLS) significantly contributes to excessive synovial hyperplasia and joint deformity in rheumatoid arthritis (RA). It has been observed that the membrane iron transporter protein, ferroportin (FPN), is commonly downregulated in tumor cells, while its overexpression can inhibit tumor cell proliferation. However, limited studies have investigated the role of iron in the pathogenesis of RA. In this study, we examined the functional relevance of FPN in RA. The expression of FPN in RA tissue specimens and primary cells was assessed using western blotting and RT-PCR. An adjuvant-induced arthritis (AIA) rat model was established to further validate the expression level of FPN. Phenotypic analysis of FLS cell proliferation was performed via CCK-8, clonogenic formation, and cell scratch assays. The involvement of membrane iron transporter proteins was analyzed through RNAseq and reactive oxygen species (ROS) detection. The results demonstrated decreased expression of FPN in the synovial tissue of RA patients compared to the normal group. Overexpression of FPN can inhibit RA-FLS proliferation and migration by suppressing the PI3K/AKT pathway, and this effect is associated with the elevation of ROS levels. Our findings suggest that the downregulation of FPN may contribute to the pathogenesis of RA, indicating a potential role of iron dysregulation in this disease, and FPN regulates the proliferation and migration of FLS by promoting the levels of ROS in FLS as well as suppressing the PI3K/AKT signaling pathway. These results suggest that FPN could be a potential target for alleviating joint damage in RA.