Diabetic retinopathy from the perspective of programmed cell death: Focusing on apoptosis, pyroptosis, and necroptosis.

Diabetic retinopathy (DR), characterized by vascular damage and chronic inflammation, poses a significant threat to vision. Programmed cell death (PCD) plays a crucial role in DR pathogenesis, with apoptosis, pyroptosis, and necroptosis being extensively implicated in retinal cell loss. Current research lacks a systematic analysis of the temporal dynamics of these PCD modalities. This review focuses on apoptosis, pyroptosis, and necroptosis to elucidate their stage-specific contributions to DR progression. Apoptosis primarily occurs in the nonproliferative DR (NPDR) phase and drives early microvascular lesions (e.g., microaneurysms and exudates) and neurodegeneration. Pyroptosis amplifies inflammation and is predominantly activated in the proliferative DR (PDR) phase, promoting pathological angiogenesis. Necroptosis may contribute to late-stage fibrosis, although its temporal role requires further validation. Other PCD pathways (e.g., ferroptosis, cuproptosis, and disulfidptosis) are briefly discussed as potential therapeutic targets. We propose a dynamic model in which caspase-mediated crosstalk between PCD pathways orchestrates DR progression. Targeting stage-specific PCD mechanisms offers promising strategies for intervention, yet challenges in clinical translation remain owing to cellular heterogeneity and pathway interdependencies.