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The natural compound plumbagin has a wide range of pharmacological and potential therapeutic activities, although its role in neuroretina degeneration is unknown. Here we evaluated the effects of plumbagin on retina homeostasis of the fruit fly Drosophila melanogaster fed with high glucose diet, a model of hyperglycemia-induced eye impairment to study the pathophysiology of diabetic retinopathy at the early stages. To this aim, the visual system of flies orally administered with plumbagin has been analyzed at structural, functional, and molecular/cellular level as for instance neuronal apoptosis/autophagy dysregulation and oxidative stress-related signals. Our results demonstrated that plumbagin ameliorates the visual performance of hyperglycemic flies. Drosophila eye-structure, clearly altered by hyperglycemia, i.e. defects of the pattern of ommatidia, irregular rhabdomeres, vacuoles, damaged mitochondria, and abnormal phototransduction units were rescued, at least in part, by plumbagin. In addition, it reactivated autophagy, decreased the presence of cell death/apoptotic features, and exerted antioxidant effects in the retina. In terms of mechanisms favoring death/survival ratio, Nrf2 signaling activation may be one of the strategies by which plumbagin reduced redox unbalance mainly increasing the levels of glutathione-S-transferase. Likewise, plumbagin may act additively and/or synergistically inhibiting the mitochondrial-endoplasmic reticulum stress and unfolded protein response pathways, which prevented neuronal impairment and eye damage induced by reactive oxygen species. These results provide an avenue for further studies, which may be helpful to develop novel therapeutic candidates and drug targets against eye neurotoxicity by high glucose, a key aspect in retinal complications of diabetes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)