Lactylation at H3K18 drives pathological angiogenesis via metabolic-epigenetic crosstalk in ischemic retinopathy.

UNLABELLED: Ocular neovascular disease, characterized by aberrant angiogenesis in the eye, is a primary cause of global vision impairment and blindness. As the primary barrier exposed to hypoxia-related blood metabolites, endothelial cells (ECs) undergo metabolic reprogramming that drives pathological angiogenesis. However, the epigenetic mechanisms that link EC metabolic dysfunction to retinal vasculopathy remain elusive.

METHODS

Using western blotting and immunofluorescence analysis of retinal sections/whole-mounts, we confirmed increased histone 3 lactylation at lysine 18 (H3K18la). We subsequently identified downstream target genes through integrated CUT&Tag and RNA sequencing (RNA-seq), assessed their angiogenic regulatory functions using siRNA, and validated the mechanisms in vivo employing adeno-associated virus (AAV)-based gene transfer.

RESULTS

Our data indicated that histone lactylation levels were elevated in retinal vascular ECs under hypoxic conditions both in vivo and in vitro. In oxygen-induced retinopathy (OIR) retinal vascular ECs, H3K18la was the most prominent modification. Pharmacological inhibition of glycolysis suppressed H3K18la levels, concurrently abrogating EC activation and neovascularization. Combined CUT&Tag and RNA-seq analyses revealed that ETS1 was a direct transcriptional target governed by H3K18la in retinal ECs. Silencing ETS1 substantially inhibited hypoxia-induced proliferation, migration, sprouting, and tube formation in human retinal microvascular endothelial cells (HRMECs). Crucially, in vivo rescue experiments confirmed that ETS1 overexpression reversed the suppression of pathological neovascularization in OIR mice treated with AAV-Pfkfb3-RNAi.

CONCLUSIONS

Collectively, this study revealed a lactate-driven epigenetic cascade wherein H3K18la licenses ETS1-dependent pathological angiogenesis, providing a promising therapeutic avenue for ischemic retinal diseases.