circ_0002970 promotes fibroblast-like synoviocytes invasion and the inflammatory response through Hippo/YAP signaling to induce CTGF/CCN1 expression in rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation, hyperplasia, and joint destruction. Fibroblast-like synoviocytes (FLSs) are key effector cells in RA, contributing to synovial invasion, extracellular matrix degradation, and inflammatory cytokine secretion. Recent studies suggest that circular RNAs (circRNAs) regulate cellular function and disease progression, but their role in RA remains unclear. The Hippo-YAP signaling pathway governs cell proliferation, Apoptosis, and extracellular matrix remodeling, and its dysregulation is linked to RA synovial hyperplasia and inflammation. However, whether circRNAs regulate Hippo-YAP signaling in RA-FLSs has not been fully elucidated. This study investigates the role of circ_0002970 in RA progression and its regulation of the Hippo-YAP pathway.

Methods: Synovial tissues from RA patients, osteoarthritis (OA) patients, and healthy controls were collected. Differentially expressed circRNAs were identified via RNA Sequencing. The expression of circ_0002970 was validated via qRT‒PCR, FISH, and RNase R digestion assays. The functional experiments included transfection, migration/invasion assays, ELISA, and Western blotting to evaluate its role in RA-FLSs.

Results: Circ_0002970 was significantly upregulated in RA-FLSs. Knockdown of circ_0002970 suppressed RA-FLS migration, invasion, and IL-6 secretion. Mechanistically, circ_0002970 knockdown downregulated the expression of Hippo-YAP pathway components (YAP, CTGF, and CCN1) and decreased the expression of MMP-9 and MMP-13, which are critical for cartilage degradation. Furthermore, verteporfin (VP)-mediated inhibition of Hippo-YAP reversed the effects of circ_0002970 overexpression.

Conclusion: These findings highlight circ_0002970 as a novel regulator of RA-FLS migration, invasion, and inflammation via the Hippo-YAP signaling pathway.