GLP-1 receptor agonists (GLP-1RAs) were initially used for glycemic control in type 2 diabetes, but studies in recent years have found that they may have potential therapeutic effects in diabetic retinopathy (DR). DR is a leading cause of vision loss in diabetes, and intricately linked to endoplasmic reticulum (ER) stress, a pathological hallmark driven by chronic hyperglycemia, oxidative stress, and inflammatory cascades. This article reviews the role of ER stress and GLP-1RAs in microvascular and neuron function, and then explores the effects of them on DR progression, emphasizing their contribution to retinal vascular dysfunction, neuroinflammation, and neuronal apoptosis. Moreover, we integrate the emerging evidence suggesting that the therapeutic potential of GLP-1 RAs in mitigating ER stress-driven retinal damage in DR. We propose that chronic hyperglycemia exacerbates ER stress, disrupts retinal redox balance and calcium signaling, leading to maladaptive unfolded protein response (UPR) activation, while GLP-1 RAs may restore proteostasis by fine-tuning PERK and IRE1α pathways, thereby alleviating retinal dysfunction. Although direct mechanistic links between GLP-1RAs mediated ER stress reduction and clinical outcomes in DR remain unresolved, this review underscores the need to elucidate these connections as pivotal for advancing targeted therapies. By contextualizing ER stress within both metabolic dysregulation and adaptive cellular responses, this synthesis aims to bridge current knowledge gaps and inspire novel strategies leveraging GLP-1RAs to enhance retinal resilience in DR, ultimately informing future preclinical and clinical investigations. Future research should prioritize preclinical validation of ER stress-targeting strategies and clinical translation of GLP-1RAs to improve visual outcomes in DR, ultimately bridging the gap between molecular insights and therapeutic innovation.
