Astaxanthin and Related Carotenoids as a Dual Modulator of Nrf2 and NF-κB in Bisretinoid-Induced Retinal Damage: Mechanistic Rationale and Evidence Gaps

The retinal pigment epithelium (RPE) plays a key role in age-related macular degeneration (AMD). With aging, bisretinoids such as A2E accumulate in RPE lysosomes, and this accumulation is markedly accelerated by ABCA4 loss of function, which impairs the clearance of retinaldehyde from photoreceptor disc membranes. A2E acts as a blue-light photosensitizer, generating reactive oxygen species that cause oxidative stress, lysosomal impairment, and mitochondrial dysfunction. This oxidative burden disrupts the balance between Nrf2-mediated antioxidant defense and NF-κB-driven inflammation. Astaxanthin, a marine-derived xanthophyll carotenoid, may regulate this balance by activating Nrf2/ARE-mediated cytoprotective responses and suppressing NF-κB-dependent inflammation. This review summarizes mechanistic, preclinical, and clinical evidence for astaxanthin’s protective effects on RPE cells, with emphasis on bisretinoid-induced retinal injury. Astaxanthin reduces oxidative stress, inhibits NF-κB activity, and enhances Nrf2-dependent antioxidant defenses in hydrogen peroxide-, light-, and ischemia-induced retinal damage; however, because these models do not directly reproduce A2E-mediated phototoxicity, A2E-specific protection remains an untested hypothesis. Standardized A2E-specific models are needed to determine whether these protective effects extend to A2E and its photoproducts. Clinical evidence is also limited and largely based on multi-carotenoid formulations, which prevents the isolation of the effects of astaxanthin.