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Sphingosine-1-Phosphate-derived 2-Hexadecenal is a central mediator of ocular neovascularization by inhibiting Sphingosine-1-Phosphate receptor 5
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Sphingosine-1-Phosphate-derived 2-Hexadecenal is a central mediator of ocular neovascularization by inhibiting Sphingosine-1-Phosphate receptor 5
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Journal Article
Sphingosine-1-Phosphate-derived 2-Hexadecenal is a central mediator of ocular neovascularization by inhibiting Sphingosine-1-Phosphate receptor 5
2026
Overview
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.
Sphingolipids mediate inflammation, although the role of lipid aldehyde 2-HD is poorly understood. Here, the authors show ALDH3B1 detoxifies 2-HD to protect retinal vasculature, with 2HD accumulation causing vascular abnormalities.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 49
/ 49/39
/ 59
/ 59/5
/ 64
/ 64/116
/ 82/103
/ Animals
/ CRISPR
/ Diabetic Retinopathy - genetics
/ Diabetic Retinopathy - metabolism
/ Diabetic Retinopathy - pathology
/ Enzymes
/ Fibrosis
/ Humanities and Social Sciences
/ Humans
/ Lipids
/ Lysophospholipids - metabolism
/ Neovascularization, Pathologic - metabolism
/ Proteins
/ Retina
/ Retinal Neovascularization - genetics
/ Retinal Neovascularization - metabolism
/ Retinal Neovascularization - pathology
/ Retinal Vessels - metabolism
/ Science
/ Sphingosine - analogs & derivatives
/ Sphingosine-1-Phosphate Receptors - antagonists & inhibitors
/ Sphingosine-1-Phosphate Receptors - genetics
/ Sphingosine-1-Phosphate Receptors - metabolism
/ Vascular endothelial growth factor
