Jing Rongyue, Chen Yueyue, Xu Meimei, Zou Xudan, Wu Suling
Department of Rheumatology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, 210022, China.
Graduate School, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
Sci Rep. 2025 Jun 6;15(1):19871. doi: 10.1038/s41598-025-03818-7.
Rheumatoid arthritis (RA) constitutes a chronic, progressive autoimmune disease, and effective treatment of RA remains a challenge. Due to the multiple side effects and "therapeutic ceiling" effect of current RA medications, it is essential to find natural alternatives and explore their mechanisms of action in RA. In this study, we analyzed the targets of action and signaling pathways of gentiopicroside (GEN) in RA using network pharmacology and validated them through molecular docking and experimental approaches. A collagen-induced arthritis (CIA) rat model was employed to analyze the role of GEN in influencing RA joint pathology and related angiogenic factors. Additionally, cellular experiments were conducted to assess the proliferation, migration, and tubular structure formation ability of endothelial progenitor cells (EPCs). Western blotting was used to detect the protein expression of CXCL12 and CXCR4. Network pharmacological analyses revealed that GEN exerts multiple effects on RA therapy by modulating multiple pathways. Combined with literature analysis and molecular docking data modeling, GEN was found to intervene in RA by regulating CXCL12 and CXCR4. In CIA rats, GEN inhibited the expression of HIF-1α, CXCL12, VEGF-A, and Ang-2, and attenuated the pathology associated with aberrant neovascularization in the knee joint. Cellular experiments confirmed that GEN could inhibit the proliferation, migration, and tubular structure formation ability of EPCs induced by high-mobility group box 1 (HMGB1), and could inhibit the formation of abnormal neovascularization by interfering with CXCL12 and CXCR4. GEN demonstrates a significant effect in inhibiting abnormal neovascularization and can regulate CXCL12 and CXCR4 to intervene in the pathological progression of RA. This study provides a novel approach for the treatment of RA and a theoretical foundation for further research.
类风湿关节炎（RA）是一种慢性、进行性自身免疫性疾病，对其进行有效治疗仍然是一项挑战。由于目前RA药物存在多种副作用和“治疗天花板”效应，寻找天然替代物并探索其在RA中的作用机制至关重要。在本研究中，我们使用网络药理学分析了龙胆苦苷（GEN）在RA中的作用靶点和信号通路，并通过分子对接和实验方法进行了验证。采用胶原诱导性关节炎（CIA）大鼠模型分析GEN对RA关节病理及相关血管生成因子的影响。此外，进行细胞实验以评估内皮祖细胞（EPCs）的增殖、迁移和管状结构形成能力。采用蛋白质印迹法检测CXCL12和CXCR4的蛋白表达。网络药理学分析表明，GEN通过调节多种途径对RA治疗发挥多种作用。结合文献分析和分子对接数据建模，发现GEN通过调节CXCL12和CXCR4干预RA。在CIA大鼠中，GEN抑制HIF-1α、CXCL12、VEGF-A和Ang-2的表达，并减轻膝关节异常新生血管形成相关的病理变化。细胞实验证实，GEN可抑制高迁移率族蛋白B1（HMGB1）诱导的EPCs的增殖、迁移和管状结构形成能力，并可通过干扰CXCL12和CXCR4抑制异常新生血管形成。GEN在抑制异常新生血管形成方面具有显著作用，并可调节CXCL12和CXCR4干预RA的病理进程。本研究为RA的治疗提供了一种新方法，并为进一步研究奠定了理论基础。
