Sphingosine-1-Phosphate-derived 2-Hexadecenal is a central mediator of ocular neovascularization by inhibiting Sphingosine-1-Phosphate receptor 5.
鞘氨醇-1-磷酸衍生的2-十六碳烯醛通过抑制鞘氨醇-1-磷酸受体5，在眼部新生血管形成中发挥着关键的介质作用。
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 Nawroth, Jens Kroll (2026) Sphingosine-1-Phosphate-derived 2-Hexadecenal is a central mediator of ocular neovascularization by inhibiting Sphingosine-1-Phosphate receptor 5. Nat Commun (IF: 15.7) 1 区 17(1)
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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.© 2026. The Author(s).
鞘氨醇-1-磷酸 (S1P) 是一种重要的鞘脂介质，通过调控血管生成、炎症和纤维化，在血管系统和新生血管性眼病中发挥关键作用。五种 S1P 受体 (S1PR) 是重要的治疗靶点，目前已有多种靶向 S1PR 的药物投入临床应用或正在进行临床试验。然而，其主要代谢产物——活性脂质醛 2-十六碳烯醛 (2-HD) 的血管功能仍未被充分研究。本研究表明，醛脱氢酶 ALDH3B1 的缺失会损害 2-HD 的解毒作用，导致斑马鱼视网膜血管异常，但并不影响躯干血管。机制研究表明，多组学分析揭示，2-HD 的积累会破坏铁稳态，并通过与 S1PR5 直接相互作用诱导铁死亡。这一发现得到了单细胞RNA测序和人视网膜新生血管样本RNA测序的整合分析的支持，并将S1PR5确定为一个具有临床意义的靶点。这些发现揭示了S1P衍生的2-HD在血管系统和视网膜血管稳态中先前未被认识的作用，提示靶向S1PR5可能为糖尿病视网膜病变提供一种治疗策略。© 2026. 作者。
Links
http://www.ncbi.nlm.nih.gov/pubmed/41980976http://dx.doi.org/10.1038/s41467-026-71792-3
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