ALKBH3 inhibition normalizes neovessels by reprogramming endothelial fate in diabetic microvasculopathy.
YC, Z., ZQ, D., SY, X., JY, C., MH, C., BQ, L., Y, W., YY, W., XY, L., & XZ, L. (2026). ALKBH3 inhibition normalizes neovessels by reprogramming endothelial fate in diabetic microvasculopathy.. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.2602779123
YC Z, ZQ D, SY X, JY C, MH C, BQ L, et al. ALKBH3 inhibition normalizes neovessels by reprogramming endothelial fate in diabetic microvasculopathy.. Proceedings of the National Academy of Sciences of the United States of America. 2026; doi: 10.1073/pnas.2602779123
YC Z, ZQ D, SY X, et al. ALKBH3 inhibition normalizes neovessels by reprogramming endothelial fate in diabetic microvasculopathy.[J]. Proceedings of the National Academy of Sciences of the United States of America. 2026. DOI: 10.1073/pnas.2602779123.
@article{yc2026,
author = {Zhang YC and Ding ZQ and Xu SY and Chen JY and Chen MH and Luo BQ and Wang Y and Wu YY and Lv XY and Liu XZ},
title = {ALKBH3 inhibition normalizes neovessels by reprogramming endothelial fate in diabetic microvasculopathy.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
doi = {10.1073/pnas.2602779123},
note = {PMID: 42627826},
}
TY - JOUR AU - Zhang YC AU - Ding ZQ AU - Xu SY AU - Chen JY AU - Chen MH AU - Luo BQ AU - Wang Y AU - Wu YY AU - Lv XY AU - Liu XZ TI - ALKBH3 inhibition normalizes neovessels by reprogramming endothelial fate in diabetic microvasculopathy. T2 - Proceedings of the National Academy of Sciences of the United States of America PY - 2026 DO - 10.1073/pnas.2602779123 AN - PMID:42627826 ER -
Diabetic microvasculopathy is a serious diabetes complication, with diabetic retinopathy (DR) being a leading cause of blindness worldwide due to immature, leaky neovessels. Antiangiogenic therapies merely suppress neovascularization, leaving the retina oxygen-starved and prone to regrowth. Thus, therapies that stabilize aberrant neovessels are needed. We identify the RNA demethylase ALKBH3 as an epitranscriptional driver of diabetic microvasculopathy. Upregulated ALKBH3 in diabetic vascular endothelial cells promoted a pathological shift to an unstable, pro-angiogenic phenotype, disrupting blood-retinal barrier and forming immature neovessels, which impaired vision. Conversely, removing ALKBH3 protected against this. Mechanistically, ALKBH3 demethylated BMP2 mRNA to increase its stability via YTHDF2. We further developed a neovasculature-targeting nanoparticle delivering the ALKBH3 inhibitor HUHS015, which normalized retinal neovascularization by simultaneously limiting growth and promoting maturation. It acted synergistically with vascular endothelial growth factor (VEGF) blockade, suggesting potential for anti-VEGF-resistant cases. Our work defines ALKBH3 as a key mediator of diabetic microvasculopathy and supports a VEGF-independent therapeutic paradigm that shifts the focus from vessel suppression to active normalization.