Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
Department of Ophthalmology, The Affiliated Hospital of Nantong University, Nanjing 226000, China.
Oxid Med Cell Longev. 2022 Aug 31;2022:9004738. doi: 10.1155/2022/9004738. eCollection 2022.
Accumulating evidence has suggested the significant role of long noncoding RNAs (lncRNA) in regulating ferroptosis, while its regulatory mechanism in diabetic retinopathy (DR) remains unelucidated. In this work, we first demonstrated that lncRNA zinc finger antisense 1 (ZFAS1) is upregulated in high glucose-cultured human retinal endothelial cells (hRECs) and ZFAS1 inhibition attenuated high glucose- (HG-) induced ferroptosis, which was evidenced by cell viability, total iron and ferrous iron levels, reactive oxygen species (ROS) level, and Glutathione Peroxidase 4 (GP4) expression detection. Mechanistically, we validated that ZFAS1 may act as a competing endogenous RNA by competitively binding with microRNA-7-5p (miR-7-5p) and modulating the expression of its downstream molecule acyl-CoA synthetase long-chain family member 4 (ACSL4), which is now identified as a classic driver gene of ferroptosis process. In conclusion, our results demonstrate that HG-induced ZFAS1 elevation activates ferroptosis in hRECs and the ZFAS1/miR-7-5p/ACSL4 axis may serve as a therapeutic target for endothelial dysfunction in DR.
越来越多的证据表明，长非编码 RNA（lncRNA）在调控铁死亡中起着重要作用，但其在糖尿病视网膜病变（DR）中的调节机制尚不清楚。在这项工作中，我们首先证明了 lncRNA 锌指反义 1（ZFAS1）在高糖培养的人视网膜内皮细胞（hRECs）中上调，ZFAS1 抑制可减弱高糖诱导的铁死亡，这可以通过细胞活力、总铁和亚铁水平、活性氧（ROS）水平和谷胱甘肽过氧化物酶 4（GP4）表达检测来证实。从机制上讲，我们验证了 ZFAS1 可能通过与 microRNA-7-5p（miR-7-5p）竞争性结合并调节其下游分子长链酰基辅酶 A 合成酶家族成员 4（ACSL4）的表达来发挥竞争性内源性 RNA 的作用，ACSL4 现在被确定为铁死亡过程中的经典驱动基因。总之，我们的结果表明，HG 诱导的 ZFAS1 升高激活了 hRECs 中的铁死亡，ZFAS1/miR-7-5p/ACSL4 轴可能成为 DR 内皮功能障碍的治疗靶点。
