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IF: 10.7
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Lactylation-Boosted m5C RNA Modification Drives Choroidal Neovascularization

Published:2 October 2025 DOI: 10.34133/research.0913 PMID: 41049616
Sipeng Zuo,?Lin Li,?Jieling Tang,?Fuxiang Ye,?Sok,?Yan Liu,?Shengfang Ge,?Renbing Jia,?Xianqun Fan,?Peiwei Chai,?Linna Lu

Abstract

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.

Substances (26)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Lactic acid 50-21-5 C3H6O3 1151 suppliers $6.00-$4275.24
Lactic acid 50-21-5 C3H6O3 1151 suppliers $6.00-$4275.24
Lactic acid 50-21-5 C3H6O3 1151 suppliers $6.00-$4275.24
Lactic acid 50-21-5 C3H6O3 1151 suppliers $6.00-$4275.24
2-Deoxy-D-glucose 154-17-6 C6H12O5 736 suppliers $6.00-$176562.00
2-Deoxy-D-glucose 154-17-6 C6H12O5 736 suppliers $6.00-$176562.00
2-Deoxy-D-glucose 154-17-6 C6H12O5 736 suppliers $6.00-$176562.00
2-Deoxy-D-glucose 154-17-6 C6H12O5 736 suppliers $6.00-$176562.00
N-(2-[P-BROMOCINNAMYLAMINO]ETHYL)-5-ISOQUINOLINESULFONAMIDE HYDROCHLORIDE 127243-85-0 C20H20BrN3O2S 172 suppliers $25.00-$1529.00
N-(2-[P-BROMOCINNAMYLAMINO]ETHYL)-5-ISOQUINOLINESULFONAMIDE HYDROCHLORIDE 127243-85-0 C20H20BrN3O2S 172 suppliers $25.00-$1529.00

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