Phototoxicity and Oxidative Stress in Retinal Pigment Epithelium: Potential Activation of the Keap1/Nrf2/HO-1 Defense Axis by East Asian Natural Antioxidants—A Review

Age-related macular degeneration (AMD) is a leading cause of irreversible blindness, a condition significantly exacerbated by a rapidly aging global population. This demographic shift presents a severe clinical and public health crisis. Early AMD pathogenesis involves the accumulation of the lipofuscin fluorophore, A2E, within the retinal pigment epithelium (RPE). Upon blue light exposure, A2E oxidation triggers a synergistic cascade of oxidative, carbonyl, and inflammatory stresses, ultimately culminating in RPE cell apoptosis. As current medications primarily target late-stage AMD (such as anti-VEGF therapies for neovascular AMD and complement inhibitors for geographic atrophy) and carry adverse effects, developing early-stage preventative strategies is critical. Unlike previous reviews that broadly cover general oxidative stress or generic Nrf2 activators, this review establishes a precise pathogenic framework centered on A2E photo-oxidation and its downstream cascade in RPE cells. We elucidate the mechanisms underlying A2E- and blue light-induced phototoxicity, emphasizing the protective role of the Keap1/Nrf2/HO-1 antioxidant defense axis in restoring cellular redox homeostasis. Furthermore, we highlight the protective effects and therapeutic potential of diverse natural antioxidants—spanning terrestrial phytochemicals, marine bioactives, and specialized lipid mediators—that counteract retinal stress through multi-target mechanisms. We also critically address the translational gap between high-concentration in vitro bioactivity and in vivo ocular bioavailability, focusing on targeted nano-drug delivery systems (DDS). Integrating these bioactive compounds to strengthen antioxidant defenses and resolve chronic inflammation represents a promising translational avenue for future clinical investigations in early AMD management.