Kaempferol's Therapeutic Applications and Mechanistic Insights in Ocular Diseases: Current Progress, Challenges, and...

Kaempferol is a natural flavonol compound widely present in various single-herb remedies and compound formulations used for the treatment of ocular diseases. Despite its inherent pharmaceutical limitations, accumulating evidence indicates that kaempferol exerts broad protective effects against diverse ocular disorders through multiple biological pathways, highlighting its potential as a multi-target therapeutic candidate in ophthalmology. However, current evidence regarding kaempferol-based ophthalmic applications remains fragmented across different ocular diseases and mechanistic investigations, and a comprehensive evaluation of its therapeutic potential, translational challenges, and existing limitations is still lacking. This review systematically summarizes the research progress on kaempferol in the treatment of eye diseases, encompassing its source distribution, structural characteristics, ocular delivery strategies, disease spectrum coverage, molecular mechanisms, and safety profile. By critically evaluating currently available evidence, this review further identifies unresolved issues and translational barriers that hinder the clinical application of kaempferol in ophthalmology. Regarding delivery strategies, carriers such as gelatin nanoparticles, porous bovine serum albumin membranes, platelet-derived extracellular vesicles, and polyvinylpyrrolidone-based nanocomposites have preliminarily improved ocular surface retention and corneal permeability of kaempferol in models of corneal neovascularization and alkali burns. In terms of therapeutic indications, kaempferol has demonstrated protective effects in diverse experimental models, including age-related macular degeneration (AMD), diabetic retinopathy, diabetic cataract, dry eye disease, fungal keratitis, corneal transplant rejection, acute glaucoma, and retinoblastoma. At the mechanistic level, kaempferol exerts comprehensive pharmacological actions-anti-inflammatory, antioxidant, metabolic regulation, anti-angiogenic, and immunomodulatory-by modulating multiple signaling pathways, including MAPK, NF-κB, STAT1/IRF7, Nrf2/HO-1, VEGF/PI3K/Src/Akt/ERK, aldose reductase, estrogen-related receptor alpha (ERRα), and the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome. Available safety assessments suggest that kaempferol exhibits a generally favorable safety profile across ocular, cellular, systemic, and genetic evaluations. Despite these advances, the clinical translation of kaempferol in ophthalmology remains limited by insufficient clinical and pharmacokinetic evidence, underdeveloped targeted delivery strategies, and a lack of integrated understanding of its molecular basis in ocular protection. By systematically integrating evidence from ocular disease models, molecular mechanisms, delivery strategies, and safety evaluations, this review bridges fragmented knowledge regarding kaempferol-based ophthalmic applications and provides an integrated framework for understanding its therapeutic potential and translational prospects. Overall, this review highlights kaempferol as a promising multi-target therapeutic candidate for ocular diseases and provides insights into its future translational development.