FTO overexpression inhibits the invasion and migration of rheumatoid arthritis fibroblast-like synoviocytes by suppressing miR-126-5p

Aim Rheumatoid arthritis (RA) inflicts chronic joint inflammation, leading to cartilage damage and potential disability. This study delves into the impact of fat mass and obesity-associated protein (FTO) on the invasion and migration of fibroblast-like synoviocytes (FLSs) in RA, aiming to identify a novel target for RA treatment. Methods RA-FLSs and control-FLSs from RA patients and healthy controls were isolated and cultured. An FTO overexpression vector was constructed and transfected into RA-FLSs, with subsequent measurement of FTO, miR-126-5p, and FOXO3 expression levels using quantitative real-time polymerase chain reaction or western blot assays. The proliferation, invasion, and migration capabilities of RA-FLSs were assessed. The total m6A modification of cellular mRNA was quantified. The interaction between m6A and DiGeorge syndrome critical region 8 (DGCR8) on pri-miR-126-5p was evaluated using methylated RNA immunoprecipitation. The binding relationship between miR-126-5p and FOXO3 3 ' UTR sequence was verified. Results FTO was downregulated in RA-FLSs. FTO overexpression inhibited the invasion and migration of RA-FLSs. FTO reduced the m6A modification level of pri-miR-126-5p in RA-FLSs, inhibiting miR-126-5p expression by reducing the binding of DGCR8 to pri-miR-126-5p. miR-126-5p targeted and inhibited FOXO3 expression. Overexpression of miR-126-5p or FOXO3 knockdown could partially reverse FTO overexpression's inhibitory effect on the invasion and migration of RA-FLSs. Conclusion FTO overexpression curtailed miR-126-5p by diminishing the m6A modification level of pri-miR-126-5p, subsequently enhancing FOXO3 expression and restraining the invasion and migration of RA-FLSs. The m6A modification of pri-miR-126-5p promotes DGCR8 to shear pri-miR-126-5p and thus increase the expression of mature miR-126-5p. miR-126-5p targets and inhibits the expression of FOXO3 to promote the invasion and migration of RA-FLS, and FTO inhibits the above process by decreasing the m6A modification of pri-miR-126-5p to inhibit the invasion and migration of RA-FLS.image