PUBLICATION
Sphingosine-1-Phosphate-derived 2-Hexadecenal is a central mediator of ocular neovascularization by inhibiting Sphingosine-1-Phosphate receptor 5
- Authors
- Qian, X., Ge, R., Chu, Y., Kuang, T., Zhang, X., Bennewitz, K., Lou, B., Hao, W., Ast, V., Klinke, G., Poschet, G., Morgenstern, J., Fleming, T., Hausser, I., Szendroedi, J., Nawroth, P.P., Kroll, J.
- ID
- ZDB-PUB-260415-9
- Date
- 2026
- Source
- Nature communications 17: (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
- none
- PubMed
- 41980976 Full text @ Nat. Commun.
Citation
Qian, X., Ge, R., Chu, Y., Kuang, T., Zhang, X., Bennewitz, K., Lou, B., Hao, W., Ast, V., Klinke, G., Poschet, G., Morgenstern, J., Fleming, T., Hausser, I., Szendroedi, J., Nawroth, P.P., Kroll, J. (2026) Sphingosine-1-Phosphate-derived 2-Hexadecenal is a central mediator of ocular neovascularization by inhibiting Sphingosine-1-Phosphate receptor 5. Nature communications. 17:.
Abstract
Sphingosine-1-phosphate (S1P) is a crucial sphingolipid mediator in vasculature and neovascular eye diseases by controlling angiogenesis, inflammation and fibrosis. Five S1P receptors (S1PRs) are key therapeutic targets, with several S1PR-targeted drugs already in clinical use or trials. However, the vascular function of its major metabolic product, the reactive lipid aldehyde 2-hexadecenal (2-HD), remains unexplored. Here, we show that loss of the aldehyde dehydrogenase ALDH3B1 impairs 2-HD detoxification and leads to retinal vascular abnormalities in zebrafish, without affecting the trunk vasculature. Mechanistically, multi-omics analyses reveal that 2-HD accumulation disrupts iron homeostasis and induces ferroptosis by directly interacting with S1PR5. This finding is supported by integrative analyses of single-cell RNA sequencing and RNA sequencing from human neovascular retinal samples, identifying S1PR5 as a clinically relevant target. These findings uncover a previously unrecognized role of S1P derived 2-HD in vasculature and retinal vascular homeostasis, suggesting that targeting S1PR5 could offer a therapeutic strategy for diabetic retinopathy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping