Piperine alleviates retinal ischemic injury by mediating the APE1 signaling

Ischemic retinal damage is the most common cause of severe vision impairment and blindness. Anti-vascular endothelial growth factor (anti-VEGF) agents have transformed the treatment of retinal ischemic disorders and have become the cornerstone therapy for these conditions. Nonetheless, the risk for systemic and ocular adverse effects necessitates careful consideration. Meanwhile, the therapeutic potential of natural compounds for ischemic retinal injury is increasingly attracting attention. In this study, piperine (PIP), a natural compound derived from pepper, was found to reduce apoptosis by reducing the severity of retinal and optic nerve ischemic damage. However, the precise pharmacological mechanisms of PIP are yet to be fully elucidated. Molecular docking (MD) studies, MD simulations, and surface plasmon resonance experiments were conducted to determine the molecular targets of PIP. Our data revealed that PIP can bind to apurinic/apyrimidinic endonuclease 1 (APE1), thereby inhibiting apoptosis by decreasing the expression of caspase-9 and caspase-3 and regulating the mitochondrial pathway. In summary, PIP may directly targets the APE1 protein and further regulates the caspase-9/caspase-3 axis to provide neuroprotection against ischemic retinal injury.