Microglia disulfidptosis contributes to worsening of diabetic retinopathy induced by acute hypoglycemia.

The early worsening of diabetic retinopathy (DR) is associated with rapid declines in blood glucose levels during diabetes treatment, yet its pathogenesis remains poorly understood. This study aims to investigate the role of acute hypoglycemia (AH) in microglial disulfidptosis and the underlying mechanisms during DR progression. Using single-cell sequencing, we identified SLC7A11high microglia. Glucose deprivation further upregulated SLC7A11 expression in microglia, leading to excessive cystine uptake, NADPH depletion, and disulfide stress, which also activated Rac1-WRC signaling, driving F-actin contraction and plasma membrane detachment, ultimately inducing disulfidptosis and elevating pro-inflammatory cytokine levels in microglia. In vivo, SLC7A11 was highly expressed by retinal microglia in AH mice, and AH exacerbated retinal vascular leakage, structural disorganization, and microglial cell death in the retinas of AH mice. Collectively, these findings suggest that glucose deprivation triggers microglial disulfidptosis, providing a potential mechanism by which hypoglycemia exacerbates early DR deterioration, and identifying possible therapeutic targets for intervention.