Melatonin protects retinal pigment epithelium cells against ferroptosis in AMD via the PI3K/AKT/MDM2/P53 pathway

Oxidative stress-prompted degeneration of the retinal pigment epithelium (RPE) notably contributes to the onset of age-related macular degeneration (AMD). However, the pathways leading to RPE deterioration and possible preventative strategies are not yet completely comprehended. Our research identified that Aβ1-40, a primary variant of Amyloid beta and a significant constituent of drusen, can trigger ferroptosis in RPE.Melatonin, on the other hand, can inhibit the oxidative stress and ferroptosis induced by Aβ1-40 in RPE cells. Melatonin has a protective effect on Aβ1-40-induced AMD, significantly improving the structure of the mouse retina and RPE layer,and facilitating the restoration of visual function. Network pharmacology methods revealed that the potential targets of melatonin for AMD are closely related to ferroptosis. KEGG pathway enrichment analysis indicated that the predominant pathways are significantly associated with the PI3K/AKT/MDM2/P53 signaling pathway.Knocking down the specific expression of MDM2 can significantly weaken the effect of melatonin in inhibiting oxidative stress and ferroptosis. These studies demonstrate that melatonin can suppress cell death by ferroptosis in RPE via the PI3K/AKT/MDM2/P53 pathway, thereby preventing and decelerating the progression of AMD.

氧化应激诱导的视网膜色素上皮（retinal pigment epithelium, RPE）变性，显著参与年龄相关性黄斑变性（age-related macular degeneration, AMD）的发病进程。然而，介导RPE退变的具体通路及潜在防治策略仍未完全阐明。本研究发现，β淀粉样蛋白（Amyloid beta）的主要亚型Aβ1-40作为玻璃膜疣（drusen）的重要组成成分，可诱导RPE细胞发生铁死亡（ferroptosis）。而褪黑素（Melatonin）则可抑制Aβ1-40诱导的RPE细胞氧化应激与铁死亡。褪黑素对Aβ1-40诱导的AMD具有保护作用，可显著改善小鼠视网膜及RPE层结构，并促进视觉功能恢复。网络药理学（network pharmacology）分析显示，褪黑素抗AMD的潜在靶点与铁死亡密切相关。KEGG通路富集分析（KEGG pathway enrichment analysis）结果表明，其富集的核心通路显著关联PI3K/AKT/MDM2/P53信号通路。敲低MDM2的特异性表达，可显著削弱褪黑素抑制氧化应激与铁死亡的作用效果。本研究证实，褪黑素可通过PI3K/AKT/MDM2/P53通路抑制RPE细胞铁死亡，从而延缓并阻断AMD的疾病进展。