Wang Yuping, Luo Weidan, Wu Wanyu, Chen Chang, Qin Bo, Xu Xiongfei, Xu Yulin, Zeng Jianghuiyi, Wang Linna, Yang Jiujie, Ng Jerome P L, Zheng Wuyan, Yun Xiaoyun, Zhou Jie, Huang Baixiong, Law Betty Yuen-Kwan, Wong Vincent Kam-Wai
Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao; Department of Breast, Thyroid and Vascular Surgery, The Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan 646600, China.
Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao; Department of Vascular Surgery, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan 646600, China.
Pharmacol Res. 2025 Aug;218:107817. doi: 10.1016/j.phrs.2025.107817. Epub 2025 Jun 13.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammation and progressive joint destruction. Although current treatments, including conventional disease-modifying antirheumatic drugs (DMARDs) and biologics, offer therapeutic benefits, they are often associated with drug resistance and significant adverse effects with long-term use. Our previous research identified the accumulation of circulating cell-free DNA (cfDNA) as a critical pathogenic factor in RA, contributing to immune dysregulation and sustained inflammatory responses. TREX1, a key 3'-5' exonuclease responsible for degrading cytoplasmic DNA fragments, has been implicated in alleviating RA symptoms by promoting cfDNA clearance. In this study, we investigated the therapeutic potential of two natural compounds, pterostilbene (PTE) and bilobalide (BB), as novel TREX1 activators, and evaluated their anti-inflammatory efficacy in RA. Our results demonstrated that both PTE and BB significantly upregulated TREX1 expression, reduced cfDNA accumulation and cGAS-STING pathway activation, and ameliorated inflammation in the adjuvant-induced arthritis (AIA) rat model. In TREX1 conditional knockout models, these therapeutic effects were markedly attenuated, underscoring the central role of TREX1 in mediating their anti-inflammatory actions. Importantly, the combination of PTE and BB exhibited a synergistic effect, further enhancing cfDNA degradation and suppressing pro-inflammatory cytokine production. These findings suggest that targeting endogenous cfDNA clearance via TREX1 activation represents a promising therapeutic strategy for RA, with broader implications for other autoimmune and age-related inflammatory diseases.
类风湿性关节炎（RA）是一种慢性自身免疫性疾病，其特征为全身性炎症和进行性关节破坏。尽管目前的治疗方法，包括传统的改善病情抗风湿药（DMARDs）和生物制剂，具有治疗益处，但长期使用往往与耐药性和显著的不良反应相关。我们之前的研究发现，循环游离DNA（cfDNA）的积累是RA的关键致病因素，会导致免疫失调和持续的炎症反应。TREX1是一种负责降解细胞质DNA片段的关键3'-5'核酸外切酶，已被证明通过促进cfDNA清除来缓解RA症状。在本研究中，我们研究了两种天然化合物，紫檀芪（PTE）和银杏内酯（BB）作为新型TREX1激活剂的治疗潜力，并评估了它们在RA中的抗炎效果。我们的结果表明，PTE和BB均显著上调TREX1表达，减少cfDNA积累和cGAS-STING途径激活，并改善佐剂诱导的关节炎（AIA）大鼠模型中的炎症。在TREX1条件性敲除模型中，这些治疗效果明显减弱，突出了TREX1在介导其抗炎作用中的核心作用。重要的是，PTE和BB的组合表现出协同效应，进一步增强cfDNA降解并抑制促炎细胞因子的产生。这些发现表明，通过激活TREX1来靶向内源性cfDNA清除是一种有前途的RA治疗策略，对其他自身免疫性和年龄相关的炎症性疾病具有更广泛的意义。
