Therapeutic effects of natural product-based hypoxia-inducible factor inhibitors in age-related retinopathy: A narrative review

Ischemic retinopathies, including neovascular age-related macular degeneration, proliferative diabetic retinopathy, and glaucoma, are major causes of irreversible blindness in aged populations. Pathologies are mainly driven by hypoxia-induced vascular dysfunction and retinal neurodegeneration. Current anti-vascular endothelial growth factor therapies have improved clinical outcomes in the diseases above. However, anti-vascular endothelial growth factor therapy requires repeated injections and fails to clearly address the pathologic hypoxic signaling pathways. Moreover, accumulating evidence indicates that various pro-angiogenic pathways beyond vascular endothelial growth factor play an important role in disease progression, particularly in cases with incomplete responses to anti-vascular endothelial growth factor therapies. This emphasizes the necessity for effective upstream-targeted strategies for disease management. Hypoxia-inducible factors, master regulators of angiogenesis, metabolism, and survival and death, represent promising upstream therapeutic molecular targets under hypoxia and stress conditions. Sustained hypoxia-inducible factor activation promotes neovascularization, vascular leakage, inflammation, and retinal neuronal cell loss. Its inhibition may provide broader disease modification. Natural products, including polyphenols, alkaloids, and carotenoids, as well as marine metabolites, show consistent hypoxia-inducible factor-inhibitory activity across preclinical models of age-related macular degeneration, diabetic retinopathy, and glaucoma. Compounds, such as aloe-emodin, resveratrol, quercetin, curcumin derivatives, oxalomalate, ginsenosides, and honokiol, have been shown to suppress hypoxia-inducible factor-1/2α signaling, downregulate vascular endothelial growth factor expression, attenuate pathological angiogenesis, and protect retinal and/or optic nerve integrity. This review provides comprehensive current evidence on natural product-based hypoxia-inducible factor inhibitors, highlighting key bioactive compounds, novel molecular mechanisms, and therapeutic outcomes for each disease. We summarize important pathologic mechanisms, drug dosing, and therapeutic outcomes, and discuss specific translational challenges and opportunities, including bioavailability, delivery barriers, and clinical validation for upstream-targeted interventions in retinal vascular and retinal neurodegenerative diseases. By modulating the hypoxia-inducible factor/vascular endothelial growth factor axis while addressing oxidative and inflammatory stresses, these natural products offer a multifaceted therapeutic profile beyond vascular endothelial growth factor inhibition alone, supporting their potential as adjunctive or alternative strategies, although further clinical validation is required.