Zhang Ao, Wei Ting-Ting, Tan Xin, Tan Cheng-Ye, Zhuang Miao, Xie Tian-Hua, Cai Jiping, Yao Yong, Zhu Lingpeng
Department of Ophthalmology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
Center of Clinical Research, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, China.
Eur J Pharmacol. 2025 Feb 15;989:177227. doi: 10.1016/j.ejphar.2024.177227. Epub 2024 Dec 28.
Age-related macular degeneration (AMD) is the leading cause of vision loss among the elderly individuals. Retinal pigment epithelium (RPE) ferroptosis is a significant pathogenetic component in AMD. This study aims to elucidate the role and mechanisms of fatty acid desaturase 1 (FADS1) in ferroptosis as well as AMD progression.
An integrated bioinformatics analysis based on the array of data from the GEO database was conducted to identify candidates involved in ferroptosis during AMD. Subsequently, cellular and mouse models of AMD were developed using sodium iodate (NaIO) to confirm the altered expression of FADS1. After treatment with a FADS1 inhibitor, cell survival, lipid peroxidation, and indicators of AMD were assessed in vitro and in vivo models. Further, immunofluorescence, immunohistochemistry, and swept-source OCT imaging were performed to assess the impacts of pharmacological inhibition of transcription factor specificity protein 1 (Sp1) on FADS1 and ferroptosis.
FADS1 expression was upregulated in AMD patients and in vitro and in vivo models of AMD. Its pharmacological inhibition had decreased mitochondrial ROS formation, lipid peroxidation, and ferroptosis as well as increased RPE cell function in ARPE-19 cells and C57BL/6J mouse models of AMD. Mechanistically, Sp1 was identified as a key transcription factor of FADS1. Moreover, Sp1 inhibition downregulated FADS1 expression consequently attenuating FADS1-mediated ferroptosis as well as AMD phenotypes.
For the first time, we demonstrated that Sp1 regulates FADS1-mediated ferroptosis in RPE cells. Our findings provide novel insights into the progression and treatment of AMD.
年龄相关性黄斑变性（AMD）是老年人视力丧失的主要原因。视网膜色素上皮（RPE）铁死亡是AMD的一个重要致病因素。本研究旨在阐明脂肪酸去饱和酶1（FADS1）在铁死亡以及AMD进展中的作用和机制。
基于基因表达综合数据库（GEO）的数据阵列进行综合生物信息学分析，以确定AMD期间参与铁死亡的候选基因。随后，使用碘酸钠（NaIO）建立AMD的细胞和小鼠模型，以确认FADS1表达的改变。在用FADS1抑制剂处理后，在体外和体内模型中评估细胞存活率、脂质过氧化和AMD指标。此外，进行免疫荧光、免疫组织化学和扫频源光学相干断层扫描成像，以评估转录因子特异性蛋白1（Sp1）的药理抑制对FADS1和铁死亡的影响。
FADS1在AMD患者以及AMD的体外和体内模型中表达上调。其药理抑制作用降低了线粒体活性氧的形成、脂质过氧化和铁死亡，同时增强了ARPE-19细胞和C57BL/6J小鼠AMD模型中RPE细胞的功能。机制上，Sp1被确定为FADS1的关键转录因子。此外，Sp1抑制下调FADS1表达，从而减轻FADS1介导的铁死亡以及AMD表型。
我们首次证明Sp1调节RPE细胞中FADS1介导的铁死亡。我们的研究结果为AMD的进展和治疗提供了新的见解。
