Melatonin protects photoreceptor cells against ferroptosis in dry AMD disorder by inhibiting GSK-3B/Fyn-dependent Nrf2 nuclear translocation

Background: 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.Methods: We exposed 661W cells to sodium iodate (NaIO3) in vitro and treated them with different concentrations of MLT. In vivo, C57BL/6 mice were given a single caudal vein injection of NaIO3, followed by an intraperitoneal injection of MLT, and eyeballs were taken for subsequent trials.Results: We found that NaIO3 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-3 beta signaling pathway. In addition, the therapeutic effect of MLT was significantly inhibited when Nrf2 was silenced.Conclusions: Our findings provide a novel insight that NaIO3 induces photoreceptor cell ferroptosis in dry AMD and suggest that MLT has therapeutic effects by suppressing GSK-3 beta/Fyn-dependent Nrf2 nuclear translocation.