<p>Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune inflammatory joint disease. The cause of synovitis in rheumatoid arthritis involves the interaction between immune cells/macrophages and fibroblast-like synoviocytes (FLSs-RA). The impact of circular RNAs on FLSs and their role in RA pathology is still unknown. This study aimed to investigate the roles and molecular mechanisms of circular RNA FNDC3B in regulating cell injury and glucose metabolism of FLSs in RA. We demonstrated that circFNDC3B was significantly upregulated and miR-125a-5p was significantly downregulated in FLSs from RA patients. When circFNDC3B was silenced or miR-125a-5p was overexpressed, it reduced FLSs-RA glucose metabolism and increased oxidative stress-induced cell injury. Through bioinformatics analysis, RNA pull-down, and luciferase assays, it was found that circFNDC3B sponged miR-125a-5p to create a ceRNA network in FLSs-RA. The glucose metabolism rate was elevated in FLSs-RA, showing a glucose-dependent characteristic compared to normal FLSs. The enzyme hexokinase 2 (HK2), which is crucial for glucose metabolism, was identified as a direct target of miR-125a-5p in FLSs. In rescue experiments, restoring miR-125a-5p in circFNDC3B-overexpressing FLSs-RA successfully counteracted the circFNDC3B-promoted glucose metabolism and resistance to cell injury. In conclusion, this study highlighted the important roles and molecular mechanisms of circFNDC3B in accelerating glucose metabolism and preventing cell apoptosis in fibroblast-like synoviocytes during rheumatoid arthritis by modulating the miR-125a-5p-HK2 axis. Targeting the circFNDC3B-mediated glucose metabolism pathway could be a promising strategy for rheumatoid arthritis therapy.</p>