Abstract
OBJECTIVE: To investigate the expression of tumor necrosis factor-alpha (TNF-α)-regulated circular RNAs (circRNAs) in T cells from patients with rheumatoid arthritis (RA). METHODS: Jurkat cells were co-cultured with TNF-α for seven days, after which circRNA expression profiles were analyzed using next-generation sequencing and validated by real-time polymerase chain reaction. Expression levels of TNF-α-regulated circRNAs were then compared between T cells from 51 RA patients and 29 healthy controls. The biological function of specific circRNAs were further examined through RNA pull-down assays and transfection experiments. RESULTS: Twenty-one circRNAs were under-expressed in Jurkat cells following chronic TNF-α exposure. Among these, 11 circRNAs were significantly downregulated in T cells from patients with RA. The expression levels of circ-UBX domain protein 7 (UBXN7), circ-Coiled-Coil Domain Containing 134 (CCDC134), and circ-Pyridoxal Dependent Decarboxylase Domain Containing 1 (PDXDC1) were inversely correlated with Disease Activity Score-28 (DAS-28) for RA. Circ-CCDC134 was found to interact with protein phosphatase 2A regulatory subunit A alpha isoform (PPP2R1A), and suppresses PP2A activity. Overexpression of circ-CCDC134 but not its linear counterpart, enhanced phosphorylation of STAT3 and AKT, leading to increased expression of Interleukin 2, and Interferon gamma (IFN-γ). In addition, increased expression of circ-CCDC134 reversed the suppressive effect of chronic TNF-α-exposure on IFN-γ and IL-2 secretion in activated Jurkat cells. CONCLUSION: Eleven TNF-α-regulated circRNAs were significantly downregulated in RA T cells, with three showing associations with RA disease activity. Circ-CCDC134 binds to and inhibits PP2A, promoting phosphorylation of STAT3 and AKT and enhancing cytokine secretion. These findings suggest that TNF-α-regulated circRNAs contribute to T cell dysfunction in RA. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13075-026-03763-4.