Li He, Zhu Lei, Li Zhaohuai, Zhang Yihan, Zhang Genxian, Peng Xuening, Wu Dongting, Jiang Qi, Wang Rong, Jia Renbing, Zheng Song Guo, Su Wenru
Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
State Key Laboratory of Eye Health, Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200001, China.
Adv Sci (Weinh). 2025 Jun 30:e17843. doi: 10.1002/advs.202417843.
Behçet's uveitis (BU), characterized by recurrent bilateral panuveitis, is a severe manifestation of Behcet's disease (BD). However, disease-specific metabolic alterations in BU remain largely unknown. Here, untargeted metabolomics and single-cell RNA sequencing (scRNA-seq) are performed in patients with BU and healthy controls (HC). scRNA-seq data of experimental autoimmune uveitis (EAU) mice are also incorporated. The data showed an altered metabolic profile, characterized by upregulated glycolysis in BU. MYC is predicted to be a hub molecule regulating glycolysis and T cell response. Notably, it is discovered that the expression level of MYC is higher in BU compare to HC and may reflect the treatment response of BU disease. Correspondingly, the scRNA-seq data of EAU mice also reveal higher glycolysis levels and MYC expression. Further studies reveal that inhibition of MYC repressed glycolysis and exerted therapeutic effects similar to those of glycolysis inhibitors, including amelioration of EAU and repression of the abnormal response of effector T cells (T helper [Th]-1 and Th17 cells). Mechanically, inhibiting MYC disrupts the glycolysis-PI3K signaling circuit to curb the effector T cell response in uveitis. Collectively, the study indicated that MYC promoted glycolysis to fuel abnormal T-cell responses, thus therapeutically targeting MYC would provide an attractive approach for treating BU.
白塞氏葡萄膜炎（BU）以复发性双侧全葡萄膜炎为特征，是白塞氏病（BD）的一种严重表现。然而，BU中疾病特异性的代谢改变在很大程度上仍不清楚。在此，对BU患者和健康对照（HC）进行了非靶向代谢组学和单细胞RNA测序（scRNA-seq）。还纳入了实验性自身免疫性葡萄膜炎（EAU）小鼠的scRNA-seq数据。数据显示代谢谱发生改变，其特征是BU中的糖酵解上调。MYC被预测为调节糖酵解和T细胞反应的枢纽分子。值得注意的是，发现与HC相比，BU中MYC的表达水平更高，并且可能反映了BU疾病的治疗反应。相应地，EAU小鼠的scRNA-seq数据也显示出更高的糖酵解水平和MYC表达。进一步的研究表明，抑制MYC可抑制糖酵解，并产生与糖酵解抑制剂类似的治疗效果，包括改善EAU和抑制效应T细胞（辅助性T [Th]-1和Th17细胞）的异常反应。从机制上讲，抑制MYC会破坏糖酵解-PI3K信号通路，以抑制葡萄膜炎中效应T细胞的反应。总的来说，该研究表明MYC促进糖酵解以支持异常的T细胞反应，因此以MYC为治疗靶点将为治疗BU提供一种有吸引力的方法。
