ALKBH5-mediated m6A modification of ID2 mRNA promotes choroidal neovascularization and subretinal fibrosis

Choroidal neovascularization (CNV) and subretinal fibrosis are pivotal in the pathogenesis of wet age-related macular degeneration (wAMD) and contribute significantly to blindness. The role of N6-methyladenosine (m6A) modifications in the progression of wAMD remains unclear. This study identifies a significant upregulation of the RNA demethylase A-ketoglutarate dioxygenase ALKB homolog 5 (ALKBH5) in macular samples of wAMD donors. Mechanistically, ALKBH5 enhances retinal microvascular endothelial cell (RMEC) migration, angiogenesis, and endothelial-mesenchymal transition (EndMT) by upregulating DNA binding/differentiation protein 2 (ID2). Further analysis reveals that ALKBH5 interacts with the YTHDF2 binding domain of the m6A reader, which recognizes the m6A sequence on ID2 mRNA. This interaction stabilizes ID2 mRNA and modulates its m6A methylation, thereby influencing the epigenetic network in wAMD. In laser-induced CNV mouse models, ALKBH5 knockdown significantly inhibits CNV and subretinal fibrosis while protecting the retinal photoreceptor layer, thus preserving visual function. This study highlights the ALKBH5-YTHDF2-ID2 axis as a critical regulator in wAMD and suggests it as a novel therapeutic target for subretinal fibrosis in wAMD.