Quercetin improves retinal glycolysis to slow myopia progression through orchestrating the AKT/FOXO/HK2 axis

OBJECTIVES: Myopia is a major global public health issue. The retina relies on glycolysis to maintain its normal physiological functions and is vulnerable to oxidative damage. However, the effects of altered glycolysis on myopia progression remain poorly understood. This study aimed to explore how oxidative damage caused by changes in retinal glycolysis promotes myopia and evaluate the potential of quercetin in alleviating this process. METHODS: We used single-cell RNA sequencing to analyze the retinas of myopic guinea pigs, followed by proteomic and phosphoproteomic profiling to identify differentially expressed proteins. We investigated the regulatory role of the AKT/FOXO/HK2 pathway in glycolysis via coimmunoprecipitation and dual-luciferase assays. Additionally, we assessed the role of glycolysis in myopia by overexpressing HK2 and using 2-deoxy-d-glucose (2DG). The effects of neuronal injury on myopia progression were explored using Fos overexpression and knockdown. Finally, after quercetin intervention, we conducted metabolomic analysis and measured retinal mitochondrial pressure and glycolysis rate to evaluate their effects on retinal metabolism. RESULTS: Multiomics analysis showed that the AKT/FOXO/HK2 pathway suppresses glycolysis during myopia progression. Protein interaction and dual-luciferase assays confirmed that reduced glycolysis promotes oxidative phosphorylation, leading to retinal oxidative damage and accelerating the progression of myopia. Quercetin treatment inhibited the AKT/FOXO/HK2 axis, restored mitochondrial oxygen consumption and glycolysis rates, and mitigated oxidative damage, which subsequently suppressed the activation of stress-responsive Fos. Furthermore, Fos overexpression amplified retinal neuronal injury, apoptosis, and mitochondrial damage to drive myopia progression. Inhibiting Fos expression or quercetin treatment alleviated neuronal injury and apoptosis, thereby inhibiting myopia progression. CONCLUSION: Our findings suggest that quercetin may attenuate myopia progression, at least in part, by modulating the AKT/FOXO/HK2 axis to restore retinal glycolysis, thereby reducing oxidative stress and mitigating retinal neuronal damage and apoptosis. This study lays the groundwork for further exploration metabolic reprogramming in myopia pathogenesis.