海南医科大学学报2025，Vol.31Issue(21)：1610-1620,11.DOI:10.13210/j.cnki.jhmu.20241126.004
雷藤舒通过p53/SLC7A11/GPX4信号通路调控铁死亡在类风湿关节炎小鼠模型中的治疗作用及其分子机制研究
Exploration of the therapeutic efficacy and molecular mechanisms of(5R)-5-Hydroxytriptolide in modulating ferroptosis via the p53/SLC7A11/GPX4 signaling pathway in a murine model of rheumatoid arthritis
摘要
Abstract
Objective:To investigate the effects of(5R)-5-Hydroxytriptolide(LLDT-8)on ferroptosis in a murine model of rheumatoid arthritis(RA)and to elucidate its underlying mechanisms via the tumor protein 53(p53)/solute carrier family 7 mem-ber 11(SLC7A11)/glutathione peroxidase 4(GPX4)signaling pathway.Methods:A total of 40 male DBA mice were allocated into the Control,the Model,the LLDT-8(0.5 mg/kg),and the Ferroptosis inhibitor(Fer-1)(1 mg/kg)groups,with 10 mice per group.All groups except the Control received collagen type Ⅱ to induce collagen-induced arthritis(CIA).Following the suc-cessful modeling,the treatment groups were administered their respective drugs,while the Control and Model groups were ga-vaged with an equal volume of saline for 4 weeks.The key observation metrics included:the thickness of the mice's toes and clini-cal scores for arthritis;assessment of bone damage using micro-computed tomography;examination of pathological changes in joint tissues via hematoxylin-eosin staining and Sirius Red-O green staining;measurement of serum levels of MMP-3,TNF-α,IL-1β,and IL-6 using enzyme-linked immunosorbent assay;evaluation of MDA,GSH,and NADPH contents in joint tissues through colorimetric methods;detection of reactive oxygen species(ROS)in joint tissues via immunofluorescence;and analysis of SLC7A11,GPX4,and p53 protein and mRNA expression using immunohistochemistry and real-time quantitative polymerase chain reaction.Results:The Model group exhibited significant joint swelling,deformities,and increased clinical scores,along with pronounced bone destruction,synovial hyperplasia,and inflammatory cell infiltration compared to the Control group.Serum levels of MMP-3,TNF-α,IL-1β,and IL-6 were significantly elevated,while GSH and NADPH levels in joint tissues were mark-edly increased,and ROS and MDA content were significantly reduced.Notably,SLC7A11 and GPX4 protein and mRNA expres-sions were significantly upregulated,whereas p53 protein and mRNA expressions were notably downregulated(P<0.05).Com-pared to the Model group treatment with LLDT-8 led to significant improvements in joint swelling and deformities,a reduction in clinical scores,mitigation of bone destruction,and a decrease in inflammatory cell infiltration and synovial hyperplasia.Additional-ly,serum levels of MMP-3,TNF-α,IL-1β,and IL-6 were significantly lowered,while GSH and NADPH levels in joint tissues decreased,and ROS and MDA content significantly increased.The protein and mRNA expressions of SLC7A11 and GPX4 were significantly downregulated,whereas p53 protein and mRNA expressions were upregulated(P<0.05).Conclusion:LLDT-8 ef-fectively reduces synovial hyperplasia and inflammatory infiltration in CIA mice,alleviating pathological damage to joint tissues.Its mechanism may involve the modulation of the p53/SLC7A11/GPX4 signaling pathway,thereby enhancing sensitivity to fer-roptosis.关键词
类风湿关节炎/铁死亡/雷藤舒/炎症Key words
Rheumatoid arthritis/Ferroptosis/(5R)-5-Hydroxytriptolide/Inflammation分类
医药卫生引用本文复制引用
范鋆钰,姜婷,何东仪..雷藤舒通过p53/SLC7A11/GPX4信号通路调控铁死亡在类风湿关节炎小鼠模型中的治疗作用及其分子机制研究[J].海南医科大学学报,2025,31(21):1610-1620,11.基金项目
This study was supported by the National Natural Science Foundation of China(82104634) （82104634）
Research Project of Shanghai Municipal Health Commission(20214Y0165) （20214Y0165）
Youth English Training Program of the Chinese Association of Traditional Chinese Medicine(XH2024-591) （XH2024-591）
Shanghai Changning District Health Commission Nebula Plan(CNWJXY011) 国家自然科学基金资助项目(82104634) （CNWJXY011）
上海市卫生健康委员会科研项目(20214Y0165) （20214Y0165）
中华中医药学会青年培英计划资助项目(XH2024-591) （XH2024-591）
上海市长宁区卫健委星云计划资助项目(CNWJXY011) （CNWJXY011）
