Lactyl-HDAC1-Mediated Epigenetic Gating of Angiogenic Transcription via Metabolic Reprogramming [ChIP-seq]

While angiogenesis serves as a cornerstone of embryogenesis and a defining feature of pathological progression, a critical gap persists in understanding how metabolic signaling precisely converges with nuclear reprogramming to ignite vascular growth. Here, we demonstrate that glucose-derived lactate via glycolysis induces site-specific lactylation at lysine 412 (K412) of histone deacetylase 1 (HDAC1), triggering transcriptional activation of pro-angiogenic genes such as VEGFA. Mechanistically, HDAC2 forms a nuclear complex with HDAC1 to suppress its lactylation modification in the cytoplasm, whereas alanyl-tRNA synthetase (AARS1) promotes its lactylation in cytoplasm to prevent HDAC1 nuclear translocation, leading to nuclear accumulation of H3K56 acetylation and chromatin remodeling that selectively activates angiogenesis-related transcriptional programs. In zebrafish models, HDAC1-K412 mutation caused embryonic lethality, and site-specific lactylation dynamically increased during cardiac development. In the HDAC1 K412A mutation knock-in mouse model, the results showed that this site prevents vascular proliferation in the retinas of streptozotocin (STZ)-induced diabetic mice. Pharmacologically, we found that the HDAC1 activator Exifone suppressed its lactylation and inhibited vascular growth. Strikingly, Exifone attenuates pathological neovascularization in embryonic chick models and halts aberrant vascular proliferation within the retinal vasculature of STZ-diabetic mice. Our findings reveal HDAC1 lactylation as a metabolic-epigenetic nexus governing angiogenesis, providing mechanistic insights into not only obscures developmental principles but hampers therapeutic targeting of aberrant vascularization in diseases ranging from cancer to diabetes. Overall design: ChIP-seq of H3K56ac in wildtype HUVEC cells after 12-hour treatment with high glucose (25 mM) or low glucose (5 mM).