Fu Shaotian, Du Han, Ling Xiao, Wang Hanyi, Chen Jianan, Zhang Hang, Chen Wugui, Liu Chengzhao, Ma Hailong, Lin Chengshou, Ma Peixiang, Qin An
Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopedics, Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Orthopaedics, Mindong Hospital Affiliated Fujian Medical University, Ningde, Fujian, China.
Front Pharmacol. 2025 May 9;16:1565422. doi: 10.3389/fphar.2025.1565422. eCollection 2025.
Gouty arthritis is a rheumatic disease characterized by synovial inflammation and cartilage damage. Current therapeutic options for gouty arthritis, such as colchicine, primarily relieve the symptoms, which makes treatment challenging.
We employed an in vitro co-culture system of chondrocytes and macrophages to simulate gouty arthritis and screen compounds that can inhibit monosodium urate (MSU) associated macrophage inflammation and chondrocytes degeneration. We further elucidated the cuproptosis mechanism in chondrocytes by qPCR and Western blotting analyses. Both acute and chronic gouty arthritis mouse models were established to evaluate the therapeutic efficacy of candidate drugs against gouty arthritis.
MSU upregulates the expression of inflammatory cytokines in macrophages and simultaneously induces cuproptosis in chondrocytes. By screening 24 compounds, we identified syringaresinol-4-O-β-d-glucoside (SSG), a furanoid lignan, as a potent inhibitor of macrophage-mediated inflammation and chondrocyte cuproptosis. Mechanistically, SSG inhibited MSU-induced activation of the NF-κB and NLRP3 pathways in macrophages. Furthermore, SSG regulated the expression of sulfur-linked mitochondrial enzymes (e.g., DLAT) in the cuproptosis pathway, thereby inhibiting the upstream regulator FDX1 in chondrocytes. SSG not only alleviated inflammatory pain but also protected against cartilage damage and improved motor dysfunction in the mice models of acute and chronic gouty arthritis.
SSG can serve as a promising therapeutic option for gouty arthritis in clinical settings by suppressing inflammation and preserving cartilage integrity.
痛风性关节炎是一种以滑膜炎症和软骨损伤为特征的风湿性疾病。目前痛风性关节炎的治疗选择，如秋水仙碱，主要是缓解症状，这使得治疗具有挑战性。
我们采用软骨细胞和巨噬细胞的体外共培养系统来模拟痛风性关节炎，并筛选能够抑制尿酸钠（MSU）相关巨噬细胞炎症和软骨细胞退变的化合物。我们通过qPCR和蛋白质免疫印迹分析进一步阐明软骨细胞中的铜死亡机制。建立急性和慢性痛风性关节炎小鼠模型以评估候选药物对痛风性关节炎的治疗效果。
MSU上调巨噬细胞中炎性细胞因子的表达，同时诱导软骨细胞发生铜死亡。通过筛选24种化合物，我们鉴定出一种呋喃类木脂素——紫丁香树脂醇-4-O-β-D-葡萄糖苷（SSG），它是巨噬细胞介导的炎症和软骨细胞铜死亡的有效抑制剂。从机制上讲，SSG抑制MSU诱导的巨噬细胞中NF-κB和NLRP3信号通路的激活。此外，SSG调节铜死亡途径中硫连接的线粒体酶（如DLAT）的表达，从而抑制软骨细胞中的上游调节因子FDX1。在急性和慢性痛风性关节炎小鼠模型中，SSG不仅减轻了炎性疼痛，还防止了软骨损伤并改善了运动功能障碍。
SSG通过抑制炎症和维持软骨完整性，可作为临床治疗痛风性关节炎的一种有前景的治疗选择。
