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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)

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