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.