Lactylation-Boosted m⁵C RNA Modification Drives Choroidal Neovascularization

Area of Science:

• Molecular Biology
• Epigenetics
• Ophthalmology

Background:

• N5-methylcytosine (m⁵C) is a key RNA modification impacting cellular processes.
• The role of m⁵C and the NSUN2 methylase in choroidal neovascularization (CNV) is not fully understood.

Purpose of the Study:

• To investigate the mechanism linking histone lactylation, NSUN2, m⁵C modification, and CNV pathogenesis.
• To explore potential therapeutic targets for CNV.

Main Methods:

• Analysis of NSUN2 expression and m⁵C levels in normal and CNV endothelial cells (ECs).
• Investigating the effect of lactate-mediated histone lactylation on the NSUN2 promoter.
• Utilizing NSUN2 silencing and EC-specific knockout mice (Nsun2 ^-/-) to assess CNV progression.
• Employing multiomics analyses to identify downstream targets of NSUN2.

Main Results:

• NSUN2 expression and m⁵C levels were elevated in CNV-ECs, correlated with increased histone lactylation.
• NSUN2 silencing impaired EC proliferation, migration, and tube formation.
• EC-specific Nsun2-deficient mice showed reduced retinal vascular leakage.
• NSUN2 was found to increase m⁵C levels in AKAP2, activating the PKA-VEGFR2 pathway.

Conclusions:

• Histone lactylation promotes NSUN2-mediated m⁵C modification, driving CNV development.
• The NSUN2-m⁵C-AKAP2-PKA-VEGFR2 axis is a critical pathway in CNV pathogenesis.
• Targeting the interplay between histone lactylation and m⁵C RNA modification offers a novel therapeutic strategy for CNV.