Int J Biol Macromol. 2026 Jan 13:150272. doi: 10.1016/j.ijbiomac.2026.150272. Online ahead of print.
ABSTRACT
Diabetic retinopathy (DR) is a leading cause of blindness among adults worldwide, with hyperglycemia-induced oxidative stress lies at the core of its pathogenesis. This review synthesises evidence showing that elevated glucose, hypoxia and pro-inflammatory mediators act synergistically to impair the mitochondrial electron-transport chain and activate NADPH oxidase, thereby generating excess reactive oxygen species (ROS). These ROS, in turn, potentiate the polyol, protein kinase C, hexosamine and advanced-glycation end-product pathways, creating a metabolic-memory-driven vicious circle that disrupts the blood-retina barrier, promotes capillary closure and triggers neurodegenerative damage. We further delineate the ROS-dependent molecular networks underlying endoplasmic-reticulum stress, inflammation and apoptosis, and summarize preclinical and early clinical data on the efficacy of antioxidant therapies. By integrating the latest mechanistic insights with emerging intervention strategies, we propose that multi-target approaches directed at oxidative stress may attenuate DR progression and offer a rational framework for developing safe and effective retinal-protective treatments.
METHODS: We undertook a narrative review and conducted searches of the PubMed and Web of Science databases from inception to June 25, 2025, restricting results to English-language publications. The search keywords were: diabetic retinopathy, oxidative stress, reactive oxygen species, mitochondria, NADPH oxidase, endoplasmic reticulum stress, unfolded protein response, ferroptosis, and antioxidants.
INCLUSION CRITERIA: reports were eligible if they focused on diabetic retinopathy and addressed at least one of the following: oxidative stress or ROS biology; mitochondrial dysfunction; NADPH oxidase; ER stress/UPR; ferroptosis; gut-retina axis with oxidative-stress relevance; AI/ML-derived oxidative-stress or ferroptosis signatures for DR stratification; or antioxidant/ROS-targeting interventions in cellular, animal, or human studies. Both original studies (in vitro, in vivo, clinical, and trials) and reviews used for contextualization were considered.
EXCLUSION CRITERIA: we excluded non-DR ocular conditions without a clearly stated link to DR oxidative/ER-stress mechanisms; articles not in English; conference abstracts without full reports; preprints without peer review; case reports lacking mechanistic or outcome data; and opinion pieces or editorials unless they provided population-health context directly relevant to DR. Titles/abstracts and then full texts were screened independently by two authors with disagreements resolved by discussion and, when needed, consultation with a third reviewer. In keeping with the narrative nature of this review, we did not conduct a formal tool-based risk-of-bias assessment. Instead, included studies were qualitatively appraised for topical relevance to oxidative- and ER-stress mechanisms in DR, appropriateness of models and methods, and clarity of outcomes.
PMID:41539508 | DOI:10.1016/j.ijbiomac.2026.150272