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Sphingosine-1-Phosphate-derived 2-Hexadecenal is a central mediator of ocular neovascularization by inhibiting Sphingosine-1-Phosphate receptor 5

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, th...

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Auteurs principaux: Qian, Xin (Auteur) , Ge, Rui (Auteur) , Chu, Yinteng (Auteur) , Kuang, Tian (Auteur) , Zhang, Xin (Auteur) , Bennewitz, Katrin (Auteur) , Lou, Bowen (Auteur) , Hao, Weijie (Auteur) , Ast, Volker (Auteur) , Klinke, Glynis (Auteur) , Poschet, Gernot (Auteur) , Morgenstern, Jakob (Auteur) , Fleming, Thomas (Auteur) , Haußer-Siller, Ingrid (Auteur) , Szendrödi, Julia (Auteur) , Nawroth, Peter Paul (Auteur) , Kroll, Jens (Auteur)
Format: Article (Journal)
Langue:anglais
Publié: 14 April 2026
In: Nature Communications
Year: 2026, Volume: 17, Pages: 1-17
ISSN:2041-1723
DOI:10.1038/s41467-026-71792-3
Accès en ligne:Verlag, kostenfrei, Volltext: https://doi.org/10.1038/s41467-026-71792-3
Verlag, kostenfrei, Volltext: https://www.nature.com/articles/s41467-026-71792-3
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Notes sur l'auteur:Xin Qian, Rui Ge, Yinteng Chu, Tian Kuang, Xin Zhang, Katrin Bennewitz, Bowen Lou, Weijie Hao, Volker Ast, Glynis Klinke, Gernot Poschet, Jakob Morgenstern, Thomas Fleming, Ingrid Hausser, Julia Szendroedi, Peter Paul Nawroth & Jens Kroll
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Résumé: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.
Description:Online veröffentlicht: 14. April 2026
Gesehen am 12.06.2026
Description matérielle:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-026-71792-3

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