ABSTRACT: Age-related macular degeneration (AMD) is a leading cause of vision loss in the elderly, driven by retinal pigment epithelium (RPE) dysfunction, mitochondrial impairment, oxidative stress, chronic inflammation, and cellular senescence. Vutiglabridin, an orally available derivative of glabridin, has been reported to enhance mitochondrial function and mitigate metabolic stress, suggesting potential therapeutic utility in retinal aging. Here, we evaluated the efficacy and mechanism of Vutiglabridin in multiple models, including naturally aged mice representing age-associated retinal degeneration, sodium iodate (NaIO3)-induced geographic atrophy (GA), and laser-induced choroidal neovascularization (CNV). Retinal morphology and function were assessed by fundus photography, autofluorescence imaging, and electroretinography, while molecular, histological, and transcriptomic analyses were employed to investigate senescence, mitochondrial function, and inflammation. Pharmacokinetic profiling demonstrated prolonged ocular distribution of Vutiglabridin. In parallel, Paraoxonase 2 (PON2) knockdown mice were used to determine the mechanistic dependency. Vutiglabridin attenuated senescence and inflammatory markers, reduced mitochondrial ROS, and preserved retinal thickness in aged mice, while bulk RNA sequencing demonstrated partial reversal of aging-associated transcriptional signatures. In the NaIO3 model, Vutiglabridin restored mitochondrial membrane potential, enhanced mitophagy, and improved retinal function. In CNV models, it suppressed lesion growth and oxidative stress with efficacy comparable to aflibercept. Importantly, Vutiglabridin increased PON2 protein levels in vivo, and its protective effects were abolished in PON2-deficient mice, confirming a PON2-dependent mechanism. These findings establish Vutiglabridin as a promising oral therapeutic candidate for both dry and neovascular AMD, acting through PON2-mediated enhancement of mitochondrial resilience and suppression of oxidative, inflammatory, and senescent pathways.
