Lactylation-Boosted m⁵C RNA Modification Drives Choroidal Neovascularization

As a prevalent posttranscriptional RNA modification, N5-methylcytosine (m⁵C) plays a crucial role in a multitude of cellular responses and processes that govern RNA metabolism. Howbeit, a comprehensive understanding of the role and mechanism of m⁵C and the methylase NSUN2 in choroidal neovascularization (CNV) remains elusive. Herein, we revealed that histone lactylation fuels NSUN2-mediated m⁵C modification, leading to up-regulated m⁵C levels and initiates the pathological progression of CNV. First, we discovered that NSUN2 expression and m⁵C modification level were markedly higher in CNV-endothelial cells (ECs) than in normal ECs, which was driven by the augmentation of lactate-mediated histone lactylation within the NSUN2 promoter. NSUN2 silencing inhibited proliferative, migration, and tube formation activities of ECs. Importantly, compared with EC Nsun2 ^flox/flox mice, EC-specific Nsun2-deficient (EC Nsun2 ^-/-) mice displayed less retinal vascular leakage after laser induction. Through multiomics analyses, we identified that NSUN2 enhanced m⁵C level of A-kinase anchoring protein 2 (AKAP2), activating protein kinase A (PKA)-vascular endothelial growth factor receptor 2 (VEGFR2) signaling in ECs. Overall, our findings revealed that the interplay between histone lactylation and m⁵C RNA modification serves as an important pathological trigger for CNV, paving new avenues for the treatment of CNV.