Delphinidin inhibits retinal photochemical damage by regulating the cGAS-STING pathway to suppress NCOA4-mediated ferritinophagy.
Retinal photochemical damage is associated with the development of ocular diseases, yet its underlying mechanisms are incompletely defined, and therapeutic strategies are limited. Delphinidin, an anthocyanidin with broad pharmacological activities, has been demonstrated to protect against retinal damage. However, the molecular basis of this effect remains unclear. Here, we investigated the pathogenic mechanisms of light-induced retinal damage and evaluated the therapeutic potential of delphinidin. We found that intense light exposure caused photoreceptor loss, accompanied by features of ferroptosis and autophagy, including disrupted iron homeostasis, lipid peroxidation, mitochondrial impairment, autophagosome accumulation, and dysregulated expression of key molecular mediators. Co-immunoprecipitation assays of FTH1 and NCOA4, together with confocal microscopy analyses of FTH1 and LAMP1 colocalization, demonstrated that light exposure exacerbates NCOA4-mediated ferritinophagy in retinal cells, whereas delphinidin attenuated this process. RNA-seq identified abnormal STING expression, and silencing STING with siRNA effectively inhibited NCOA4-mediated ferritinophagy induced by light exposure. Delphinidin modulated the cGAS-STING pathway by reducing light-induced DNA damage. Molecular docking further suggested that delphinidin may occupy the ATP-binding pocket of cGAS, indicating a potential competitive inhibitory interaction. These findings, for the first time in the context of photochemical retinal damage, identify STING activation and NCOA4-mediated ferritinophagy as contributors to retinal ferroptosis, and highlight delphinidin as a therapeutic candidate that acts by inhibiting cGAS-STING signaling, with molecular docking, molecular dynamics simulation, and CETSA assays suggesting that delphinidin exerts its retinal protective effect by engaging the ATP-binding pocket of cGAS.