Zhang Danlei, Ren He, Xing Yiqiao, Chen Zhen
Eye Center, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, Hubei Province 430060, People's Republic of China.
ACS Omega. 2025 Jun 23;10(26):27830-27846. doi: 10.1021/acsomega.5c00595. eCollection 2025 Jul 8.
Autoimmune uveitis (AU) is a group of autoimmune-driven diseases characterized by intraocular inflammation, often leading to severe vision loss. Ferroptosis, a recently discovered form of programmed cell death, has not yet been fully explored in the pathogenesis of AU. This study aims to investigate the role of ferroptosis-related key genes in AU, providing a theoretical foundation for further mechanistic studies. We downloaded GSE198533 data set from the Gene Expression Omnibus (GEO). Through differential gene expression (DEG) analysis, weighted gene coexpression network analysis (WGCNA), and two machine learning models, TGFBR1 and ZFAS1 were identified as critical hub genes. Additionally, we validated the expression of TGFBR1 in retinal inflammation in a mouse model of experimental autoimmune uveitis (EAU) and explored its functional role. The results showed that TGFBR1 expression was significantly downregulated in EAU. Functional experiments demonstrated that TGFBR1 overexpression exacerbated retinal inflammation by promoting lipid peroxidation, downregulating GPX4 and xCT, and altering immune homeostasis by suppressing FOXP3 and enhancing IL-17A expression. Conversely, TGFBR1 inhibition via Galunisertib alleviated retinal inflammation and reversed ferroptosis- and immunity-related protein expression. These findings suggest that TGFBR1 contributes to AU pathogenesis by linking ferroptosis and immune imbalance and may serve as a potential biomarker and therapeutic target, particularly in BD-associated uveitis.
自身免疫性葡萄膜炎（AU）是一组由自身免疫驱动的疾病，其特征为眼内炎症，常导致严重视力丧失。铁死亡是一种最近发现的程序性细胞死亡形式，在AU的发病机制中尚未得到充分研究。本研究旨在探讨铁死亡相关关键基因在AU中的作用，为进一步的机制研究提供理论基础。我们从基因表达综合数据库（GEO）下载了GSE198533数据集。通过差异基因表达（DEG）分析、加权基因共表达网络分析（WGCNA）以及两种机器学习模型，确定TGFBR1和ZFAS1为关键枢纽基因。此外，我们在实验性自身免疫性葡萄膜炎（EAU）小鼠模型中验证了TGFBR1在视网膜炎症中的表达，并探讨了其功能作用。结果显示，EAU中TGFBR1表达显著下调。功能实验表明，TGFBR1过表达通过促进脂质过氧化、下调GPX4和xCT以及通过抑制FOXP3和增强IL-17A表达改变免疫稳态，从而加剧视网膜炎症。相反，通过加仑替尼抑制TGFBR1可减轻视网膜炎症，并逆转铁死亡和免疫相关蛋白表达。这些发现表明，TGFBR1通过连接铁死亡和免疫失衡促进AU发病机制，并可能作为潜在的生物标志物和治疗靶点，尤其是在与白塞病相关的葡萄膜炎中。
