Hesperidin and Hesperetin from Orange Peel Water Extract Protect against NaIO ₃ -Induced Oxidative Damage in Retinal Pigment Epithelial Cells by Modulating PI3K/Akt/HIF-1α/BNIP3 Signaling

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly, with oxidative stress a major causative factor. Orange peel, rich in polyphenols and flavonoids, possesses potent antioxidant and anti-inflammatory activities. This study evaluated the protective effects of an ultrasound-assisted aqueous extract (OPWE) of orange peel and its major components, hesperidin and hesperetin, against sodium iodate (NaIO₃)-induced retinal damage. Component identification was performed using 3D-HPLC and LC/MS, and the antioxidant capacity was determined using the DPPH and ABTS assays. <i>In vitro</i>, OPWE reduced oxidative stress, mitochondrial dysfunction, and apoptosis in NaIO₃-treated ARPE-19 cells through the PI3K/Akt and HIF-1α/BNIP3 pathways. Notably, hesperetin exhibited comparable protective effects to OPWE, restoring cell viability and inhibiting ROS production. <i>In vivo</i>, oral administration of OPWE maintained retinal morphology and function in mice induced by NaIO₃. These findings suggest that OPWE, especially hesperetin, is a promising natural candidate for preventing oxidative stress-related retinal degeneration and maintaining retinal health.