Department of Ophthalmology, the Fourth Affiliated Hospital of China Medical University, Eye Hospital of China Medical University, Key Lens Research Laboratory of Liaoning Province, Shenyang City, Liaoning Province, 110005, PR China.
Cooperation of Chinese and Western medicine branch, Jiangsu Rongjun Hospital, Wuxi, Jiangsu, PR China.
Biochim Biophys Acta Mol Basis Dis. 2024 Feb;1870(2):166969. doi: 10.1016/j.bbadis.2023.166969. Epub 2023 Nov 24.
Ferroptosis is a type of non-apoptotic cell death that relies on iron ions and reactive oxygen species to induce lipid peroxidation. This study aimed to determine whether ferroptosis exists in the pathogenesis of dry age-related macular degeneration (AMD) and to confirm that melatonin (MLT) suppresses the photoreceptor cell ferroptosis signaling pathway.
We exposed 661W cells to sodium iodate (NaIO) in vitro and treated them with different concentrations of MLT. In vivo, C57BL/6 mice were given a single caudal vein injection of NaIO, followed by an intraperitoneal injection of MLT, and eyeballs were taken for subsequent trials.
We found that NaIO could induce photoreceptor cell death and lipid peroxide accumulation, and result in changes in the expression of ferroptosis-related factors and iron maintenance proteins, which were treated by MLT. We further demonstrated that MLT can block Fyn-dependent Nrf2 nuclear translocation by suppressing the GSK-3β signaling pathway. In addition, the therapeutic effect of MLT was significantly inhibited when Nrf2 was silenced.
Our findings provide a novel insight that NaIO induces photoreceptor cell ferroptosis in dry AMD and suggest that MLT has therapeutic effects by suppressing GSK-3β/Fyn-dependent Nrf2 nuclear translocation.
铁死亡是一种依赖于铁离子和活性氧诱导脂质过氧化的非凋亡性细胞死亡。本研究旨在确定铁死亡是否存在于干性年龄相关性黄斑变性（AMD）的发病机制中，并证实褪黑素（MLT）抑制光感受器细胞铁死亡信号通路。
我们在体外将 661W 细胞暴露于碘酸钠（NaIO）中，并使用不同浓度的 MLT 进行处理。在体内，C57BL/6 小鼠经尾静脉单次注射 NaIO 后，腹腔内注射 MLT，取眼球进行后续试验。
我们发现 NaIO 可诱导光感受器细胞死亡和脂质过氧化物积累，并导致铁死亡相关因子和铁维持蛋白的表达发生变化，这些变化可被 MLT 处理所抑制。我们进一步证明，MLT 通过抑制 GSK-3β 信号通路来阻止 Fyn 依赖性 Nrf2 核转位。此外，当沉默 Nrf2 时，MLT 的治疗效果明显受到抑制。
我们的研究结果提供了一个新的见解，即 NaIO 诱导干性 AMD 中的光感受器细胞铁死亡，并表明 MLT 通过抑制 GSK-3β/Fyn 依赖性 Nrf2 核转位发挥治疗作用。
