Retinopathy, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinopathy of prematurity (ROP), are the leading cause of blindness among seniors, working-age populations, and children. However, the pathophysiology of retinopathy remains unclear. Accumulating studies demonstrate that amino acid metabolism is associated with retinopathy. This study discusses the characterization of amino acids in DR, AMD, and ROP by metabolomics from clinical and basic research perspectives. The features of amino acids in retinopathy were summarized using a comparative approach based on existing high-throughput metabolomics studies from PubMed. Besides taking up a large proportion, amino acids appear in both human and animal, intraocular and peripheral samples. Among them, some metabolites differ significantly in all three types of retinopathy, including glutamine, glutamate, alanine, and others. Studies on the mechanisms behind retinal cell death caused by glutamate accumulation are on the verge of making some progress. To develop potential therapeutics, it is imperative to understand amino acid-induced retinal functional alterations and the underlying mechanisms. This review delineates the significance of amino acid metabolism in retinopathy and provides possible direction to discover therapeutic targets for retinopathy.

Retinopathy is one of the leading causes of irreversible blindness and vision loss worldwide. Imbalanced nutrients play important roles in the pathogenesis and pathophysiology of retinal diseases. Branched-Chain Amino Acids (BCAAs), as essential amino acids, perform a variety of biological functions, including protein synthesis, glucose metabolism, lipid metabolism, inflammation, and oxidative stress in metabolic tissues of diabetes and aging-related diseases. Recently, it has been shown that BCAAs are highly related to neuroprotection, oxidative stress, inflammatory and glutamate toxicity in the retina of retinopathy. Therefore, this review summarizes the alterations of BCAA levels in retinopathy, especially diabetic retinopathy and aging-related macular disease, and the genetics, functions, and mechanisms of BCAAs in the retina as well as other metabolic tissues for reference. All of these efforts aim to provide fundamental knowledge of BCAAs for further discoveries and research on retina health based on the sensing and signaling of essential amino acids.

Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness among the working-age population. Microglia, resident immune cells in the retina, are recognized as crucial drivers in the DR process. Microglia activation is a tightly regulated immunometabolic process. In the early stages of DR, the M1 phenotype commonly shifts from oxidative phosphorylation to aerobic glycolysis for energy production. Emerging evidence suggests that microglia in DR not only engage specific metabolic pathways but also rearrange their oxidation-reduction (redox) system. This redox adaptation supports metabolic reprogramming and offers potential therapeutic strategies using antioxidants. Here, we provide an overview of recent insights into the involvement of reactive oxygen species and the distinct roles played by key cellular antioxidant pathways, including the NADPH oxidase 2 system, which promotes glycolysis via enhanced glucose transporter 4 translocation to the cell membrane through the AKT/mTOR pathway, as well as the involvement of the thioredoxin and nuclear factor E2-related factor 2 antioxidant systems, which maintain microglia in an anti-inflammatory state. Therefore, we highlight the potential for targeting the modulation of microglial redox metabolism to offer new concepts for DR treatment.