Diabetic retinopathy(DR) is a complication of diabetes that causes damage to the blood vessels in the retina,which constitutes a major and increasing health burden in developed countries.Although treatments have progressed,the development of novel treatments for patients with diabetic retinopathy remains a major research goal.The endoplasmic reticulum(ER) is the cellular organelle in which protein folding,synthesis and processing,calcium homeostasis,storage and release,detoxification of compounds,compartmentalization of the nucleus,and lipid biosynthesis occur.Endogenous or exogenous of stimuli such as hyperglycemia,hypoxia,oxidative stress,ischemic insult,disturbances in calcium homeostasis,and enhanced expression of normal and/or folding-defective proteins lead to the accumulation of unfolded proteins,a condition referred to as ER stress.ER stress triggers a signaling reaction known as the unfolded protein response(UPR) to maintain ER homeostasis,which induces adaptive programs that improve protein folding and promote quality control mechanisms,physiologically finalized to restore metabolic homeostasis and degradative pathways or can activate apoptosis when damage is sever and irreversible.Thus,therapeutic interventions that target molecules of the UPR component and reduce ER stress will be promising strategies to treat diabetic retinopathy.In this topic,we focus the recent pathological progress in understanding UPR signaling in blood-retinal barrier(BRB) by Nε-Carboxymethyllysine(CML),a major antigenic advanced glycation end products(AGEs) and its related therapeutic potential.Presenting these key mechanisms as complementary targets,we specifically emphasize the concept of molecular toxicology as potential treatment strategy to prevent or delay vision loss.We targeting the scientific evidence for this strategy from preclinical animal models,human ocular tissue analyses,and clinical information evolving in laboratory.Elucidation of Nε-Carboxymethyllysine as well as advanced glycation end products-induced precise mechanisms will help in the understanding of the complex cellular and molecular pathogenesis associated with DR.Future studies may clarify the most promising molecules to be investigated as targets for diabetic retinopathy.