Abstract
As a prevalent posttranscriptional RNA modification, N5-methylcytosine (m(5)C) 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 m(5)C and the methylase NSUN2 in choroidal neovascularization (CNV) remains elusive. Herein, we revealed that histone lactylation fuels NSUN2-mediated m(5)C modification, leading to up-regulated m(5)C levels and initiates the pathological progression of CNV. First, we discovered that NSUN2 expression and m(5)C 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 m(5)C 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 m(5)C RNA modification serves as an important pathological trigger for CNV, paving new avenues for the treatment of CNV.