Advanced Glycation End Products and Metabolic-Mechanical Coupling in Diabetic Retinopathy.

Diabetic retinopathy (DR) is a major ocular microvascular complication of diabetes mellitus and one of the leading causes of vision loss among working-age populations worldwide. Hyperglycemia-induced metabolic dysregulation has been regarded as a central mechanism underlying DR; accumulating evidence indicates that biomechanical remodeling of the retinal microenvironment also plays an important role in disease progression. Advanced glycation end products (AGEs) serve as key mediators linking metabolic stress to alterations in mechanical signaling. Through non-enzymatic glycation and covalent crosslinking of long-lived proteins, AGEs promote extracellular matrix stiffening, basement membrane thickening, and retinal vascular rigidity. These mechanical alterations can be sensed by retinal vascular cells through mechanotransduction pathways such as Piezo1, YAP/TAZ, and RhoA/ROCK signaling. Aberrant mechanical signals may further exacerbate oxidative stress, inflammatory responses, blood-retinal barrier disruption, vascular dysfunction, and pathological neovascularization. This review summarizes the role of AGEs in DR from an integrated metabolic-mechanical perspective and discusses therapeutic strategies targeting AGEs, providing new insights into potential interventions aimed at biomechanical abnormalities.