HDAC1 lactylation drives diabetic retinopathy by orchestrating a pro-angiogenic epigenetic program.

Diabetic complications, including retinopathy, are driven by hyperglycemic metabolic reprogramming and aberrant angiogenic transcription. Recent work highlights lactate accumulation and protein lactylation as key regulators, yet their underlying mechanisms in diabetic retinopathy remain unknown. Here, we report that hyperglycemia triggers aminoacyl-tRNA synthetase 1 (AARS1)-mediated lactylation of histone deacetylase 1 (HDAC1) at lysine 412. This modification sequesters HDAC1 in the cytoplasm, preventing its nuclear translocation and abrogating deacetylation of H3K56. The consequent H3K56ac increase activates transcription of the angiogenic gene vascular endothelial growth factor A (VEGFA). Disruption of the HDAC1 K412 lactylation impairs vascular morphogenesis and causes embryonic lethality in zebrafish, whereas Hdac1-K412A knockin mice are protected from pathological retinal angiogenesis in an STZ-induced diabetic model. Pharmacologically, the small molecule exifone inhibited HDAC1 lactylation, suppressing aberrant angiogenesis in diabetic mice and impairing vascular development in chick embryos. Our findings establish HDAC1 lactylation as a critical metabolic-epigenetic switch and a promising therapeutic target.