Hesperidin and Hesperetin from Orange Peel Water Extract Protect against NaIO3-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. In vitro, 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. In vivo, 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.