Mechanistic analysis of luteolin in mitigating dry age-related macular degeneration through network pharmacology and experimental validation

Dry age-related macular degeneration (AMD) ranks among the primary causes of irreversible vision loss in the elderly. Luteolin, with its diverse biological activities, has attracted significant attention as a promising candidate for intervening in dry AMD. Explore the protective effect of luteolin on dry AMD to address the unmet need for current therapeutic agents. Luteolin's target information and dry AMD-related genes were retrieved from public databases. Shared targets of luteolin and dry AMD were used to construct a protein‒protein interaction network, followed by Gene Ontology and pathway enrichment analyses. Finally, molecular docking between the active ingredient and core targets was validated. In vitro, sodium iodate was used to induce ARPE-19 cells, after which cell viability was analyzed via a Cell Counting Kit-8 (CCK-8) assay. Reactive oxygen species (ROS) levels and mitochondrial membrane potential were detected via fluorescent dye staining. In the network pharmacology analysis, a total of 213 potential therapeutic targets associated with luteolin's activity against dry AMD were identified. Among these genes, TP53, TNF, IL6, AKT1, BCL2, STAT3, JUN, and CASP3 were identified as core therapeutic targets. These targets are primarily involved in pathways including lipid and atherosclerosis, cancer-related pathways, and the AGE-RAGE signaling pathway in diabetic complications. Molecular docking analyses revealed strong binding affinities between luteolin and the core targets, validating the molecular mechanisms underlying luteolin's efficacy against dry AMD. Experimental data demonstrated that luteolin not only mitigated sodium iodate-induced reductions in ARPE-19 cell viability but also decreased intracellular ROS levels and restored mitochondrial membrane potential. Luteolin effectively enhances the viability of damaged RPE cells, reduces oxidative stress levels, and protects mitochondrial function. This protective effect is likely mediated through the coordinated action of multiple targets and pathways, highlighting luteolin's promising potential in the prevention and management of dry AMD. However, this study is limited by its sole reliance on in vitro cell validation and inability to fully reflect real in vivo effects and potential side effects.