A new 3-arylbenzofuran derivative EIE-2 reestablishes Treg-dependent tolerance in rheumatoid arthritis by targeting on Syk induced mTOR and PKCθ imbalance

作者：Ping Li, Xin Yin, Xinzhu Wen, Xuyu Li, Yuqing Wang, Hongyan Zhan, Hanqing Che, Chun‐Suo Yao, Qi Hou, Ziqian Zhang, Ruifang Zheng, Mingbao Lin · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2025.1524491 · 被引用次数：2 · 研究领域：Rheumatoid Arthritis Research and Therapies、Immune Cell Function and Interaction、T-cell and B-cell Immunology

Introduction: Dysfunctional self-tolerance is thought to play a crucial role in the onset of rheumatoid arthritis (RA) pathogenesis. Poorly functioning regulatory T cells (Tregs) lead to extreme situations where self-tolerance is robustly disrupted. However, there are many uncertainties regarding its immunosuppressive pathways, especially concerning therapeutic drugs that are still in their infancy. Therefore, deciphering potential targets and developing novel drugs to ameliorate functional Tregs deficiency appears to be an efficient therapeutic approach for controlling RA. Methods: . The role of Syk in Treg-dependent tolerance and the mechanism of EIE-2 were explored using western blotting, quantitative reverse transcription PCR (qRT-PCR) and flow cytometry. Potential mechanistic targets were further validated through siRNA knockdown and molecular docking analysis. Results: EIE-2 significantly ameliorated arthritic symptoms and pathological damage in CIA rats by reducing pro-inflammatory cytokines and increasing anti-inflammatory factors in synovium and serum, and exhibited similar therapeutic effects in carrageenan-induced pedal edema mice. Moreover, EIE-2 potently suppressed the inflammatory responses in human synoviocyte SW982 cells, primary isolated lymphocytes and CD4+ Jurkat cells. Its therapeutic potential was associated with upregulation of Tregs during the active phase and downregulation during the inactive phase of RA. Mechanistically, EIE-2 modulated the PKCθ/mTOR...