Tenascin-C Promotes Fibroblast Pathogenic Features and is Associated with Synovial Inflammation in Rheumatoid Arthritis

Despite the recognized involvement of Tenascin-C (TNC), an extracellular matrix glycoprotein induced during chronic inflammation, in tissue remodeling and inflammatory disorders, its clinical significance and functional roles in rheumatoid arthritis (RA) remain incompletely understood. Therefore, we integrated transcriptomic analyses using public datasets, clinical samples from patients with RA, and in vitro experiments in RA fibroblast-like synoviocytes (RA-FLS) to investigate the association between TNC expression and RA pathogenesis. TNC expression patterns were systematically evaluated using qRT-PCR, western blotting, immunohistochemistry, and enzyme-linked immunosorbent assays, and its relationship with clinical parameters was assessed through correlation analyses and receiver operating characteristic (ROC) curve analysis. Functional effects of TNC were further explored through gain- and loss-of-function approaches, cell proliferation, apoptosis, migration assays, and molecular analyses of autophagy- and ferroptosis-related pathways. The results demonstrated that TNC expression was significantly increased in RA synovial tissues, RA-FLS, and peripheral blood, and was positively associated with disease activity indicators, including DAS28, ESR, CRP, and disease duration. Elevated TNC exhibited potential diagnostic value for distinguishing patients with RA from healthy controls. Functional studies revealed that TNC was associated with enhanced proliferative capacity, cell-cycle progression, and reduced apoptosis susceptibility of RA-FLS. Mechanistically, TNC was found to be associated with reduced AMPK activation and increased mTOR/p70S6K signaling, accompanied by alterations in autophagy- and ferroptosis-related molecules. Transcriptomic analyses further indicated that TNC-high synovial tissues exhibited enhanced inflammatory signaling activity and increased immune cell infiltration signatures involving Th17 cells, monocytes, and M1 macrophages. In addition, proteomic screening identified ILF3 as a potential TNC-associated protein, and TNC expression was linked to altered PD-L1 expression and T-cell activation-related responses in co-culture models. Collectively, these findings identify TNC as a clinically relevant molecule associated with RA disease activity, fibroblast pathogenic phenotypes, and inflammatory immune features, suggesting that TNC may serve as a potential biomarker and therapeutic target for RA. Tenascin-C promotes RA progression by enhancing fibroblast survival and modulating immune activation through ferroptosis, autophagy, and ILF3/PD-L1 signaling.