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Sustained hyperglycemia induces early retinal neurodegeneration, manifested as the loss of retinal ganglion cells, photoreceptors, and other neuronal populations (42), through mechanisms including oxidative stress, chronic low-grade inflammation, glutamate-mediated excitotoxicity, and mitochondrial dysfunction, all of which converge to promote neuronal apoptosis (89, 90)

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Consequently, combination strategies that concurrently target metabolic adaptation and bypass signaling are emerging as effective approaches to enhance efficacy and delay resistance