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Abstract Retinal pigment epithelium (RPE) dysfunction is thought to increase the risk of the development and progression of diabetic retinopathy (DR), the leading cause of blindness. However, the molecular mechanism behind high glucose-induced RPE cell damage is still blurred. We reported that ARPE-19 exposed to 25 mM glucose for 48 h did not induce apoptosis, but senescence validated by SA-β-Gal staining, p21 expression and cell cycle distribution. High glucose also increased oxidant species that exerted a pivotal role in senescence, which could be relieved by the treatment with antioxidant N-acetylcysteine (NAC). The accumulation of lipid droplets and the increase of lipid oxidation were also observed in ARPE-19 treated with high glucose. And the supplementation of free fatty acids (FFAs) indicated that lipid metabolism was associated with the generation of hydrogen peroxide (H 2 O 2) and subsequent senescence in ARPE-19. PI3K/Akt/mTOR signaling pathway was shown to be responsible for the accumulation of intracellular lipids by regulating fatty acid synthesis, which in turn controlled senescence. Furthermore, high glucose induced autophagy in ARPE-19 with the treatment of glucose for 48 h, and autophagy inhibitor hydroxychloroquine (HCQ) or bafilomycin further aggravated the senescence, accompanying by an increase in oxidant species. Whereas, prolonged high glucose exposure inhibited autophagy and increased apoptotic cells. Experiments above provide evidence that lipid metabolism plays an important role in oxidative stressed senescence of RPE. Graphical abstract fx1 Highlights • Early high glucose exposure induces RPE cell senescence rather than apoptosis. • Fatty acid synthesis induced by high glucose through PI3K/AKT/mTOR pathway leads to lipid accumulation. • Lipid oxidation contributes to high glucose-induced RPE senescence by accumulating oxidant species. • Early high glucose treatment induces protective autophagy, while prolonged high glucose exposure inhibits autophagy. [ABSTRACT FROM AUTHOR]