Diabetic retinopathy (DR), a major complication of diabetes that causes blindness, is characterized by hyperglycemia-induced vascular dysfunction of incompletely defined mechanisms. Our study demonstrated glycolytic pathway activation in a DR rat model, which led to lactate accumulation and elevated pan lysine lactylation. Reduced lactate levels ameliorate vascular dysfunction. Global lactylome analysis of rat retinal tissues revealed 49 proteins with upregulated lactylation at 55 sites. The findings revealed that HMGA1 at lysine 74 (K74) directly promotes the transcriptional upregulation of specificity protein 1, enhancing vascular endothelial growth factor A expression and aggravating vascular dysfunction. Crucially, a K74 mutation in HMGA1 mitigated these pathological changes. This study is the first to identify HMGA1 lactylation as a critical molecular mechanism driving vascular dysfunction in DR, revealing a promising interventional target for the development of novel diagnostic markers and therapeutic strategies aimed at this specific posttranslational modification. Article Highlights Diabetic retinopathy (DR) is a major complication of diabetes that results in blindness. The underlying mechanisms of the hyperglycemia-induced vascular dysfunction that characterizes DR are not fully elucidated. Glycolytic pathway activation in DR rats causes lactate accumulation; reduced lactate levels ameliorate vascular dysfunction in DR; HMGA1 at lysine 74 (K74) lactylation promotes specificity protein 1 upregulation, enhancing vascular endothelial growth factor A expression; and K74 mutation in HMGA1 mitigates pathological changes in DR. HMGA1 lactylation is a critical molecular mechanism driving DR vascular dysfunction.
Hou et al. (Fri,) studied this question.