Yang Weili, Xu Xinyu, Xie Rongrong, Hou Zhijia, Xin Zhong, Cao Xi, Shi Tingting
Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100176, China.
Biochem Biophys Res Commun. 2025 Jul 1;768:151890. doi: 10.1016/j.bbrc.2025.151890. Epub 2025 Apr 30.
Graves' orbitopathy (GO) is a sight-threatening disease associated with thyroid dysfunction, with an unmet medical need for early diagnosis and treatment. Orbital fibroblasts (OFs) proliferation and migration play central roles in the pathogenesis of GO. Homocysteine (Hcy) has been demonstrated to be related to thyroid function, but its role in GO remains unclear. In this study, we aimed to investigate the role of Hcy in GO progression and its effects on OFs.
A total of 131 patients with Graves' disease (GD) were enrolled, of which 68 suffered from GO, with 40 having inactive GO and 28 having active GO. Serum Hcy levels were measured using ELISA assays. Primary cultured OFs were established from orbital connective tissues. Cell proliferation was quantified using CCK-8 assays, while wound healing assays were used to evaluate OFs migration. Western blotting was used to measure Akt signaling pathway.
Under a matched thyroid function state, serum Hcy levels were significantly higher in GO patients than in GD. More interestingly, active GO patients had significantly elevated Hcy levels compared to inactive GO patients. Furthermore, serum Hcy levels correlated positively with clinical activity scores in GO patients. In vitro, Hcy stimulated OFs proliferation and migration under both physiological and inflammatory conditions. Mechanistically, Hcy activated the Akt signaling pathway in OFs under these conditions.
This study supports the potential role of Hcy as a novel biomarker for GO progression. Furthermore, Hcy stimulates OFs proliferation and migration, suggesting its potential as a therapeutic target for GO treatment.
格雷夫斯眼眶病（GO）是一种与甲状腺功能障碍相关的致盲性疾病，在早期诊断和治疗方面存在未满足的医疗需求。眼眶成纤维细胞（OFs）的增殖和迁移在GO的发病机制中起核心作用。同型半胱氨酸（Hcy）已被证明与甲状腺功能有关，但其在GO中的作用仍不清楚。在本研究中，我们旨在探讨Hcy在GO进展中的作用及其对OFs的影响。
共纳入131例格雷夫斯病（GD）患者，其中68例患有GO，40例为静止期GO，28例为活动期GO。采用酶联免疫吸附测定（ELISA）法检测血清Hcy水平。从眼眶结缔组织中建立原代培养的OFs。使用细胞计数试剂盒-8（CCK-8）法对细胞增殖进行定量，同时采用伤口愈合试验评估OFs迁移。采用蛋白质免疫印迹法检测Akt信号通路。
在甲状腺功能匹配的状态下，GO患者的血清Hcy水平显著高于GD患者。更有趣的是，与静止期GO患者相比，活动期GO患者的Hcy水平显著升高。此外，GO患者的血清Hcy水平与临床活动评分呈正相关。在体外，Hcy在生理和炎症条件下均刺激OFs的增殖和迁移。机制上，在这些条件下Hcy激活了OFs中的Akt信号通路。
本研究支持Hcy作为GO进展的一种新型生物标志物的潜在作用。此外，Hcy刺激OFs的增殖和迁移，提示其作为GO治疗靶点的潜力。
