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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.

Patients with end-stage renal disease often require arteriovenous fistula (AVF) creation for hemodialysis. However, nearly 40% of patients develop aneurysmal dilatation of AVF (AVFA) after surgery, which can lead to prolonged bleeding at puncture sites, increased infection risk, and even potential rupture. Despite its high incidence, research on AVFA remains remarkably limited. This study makes an innovative discovery by establishing a link between AVFA formation and alternative splicing of fibronectin (FN), a crucial extracellular matrix component. Specifically, we demonstrate that increased inclusion of the EDA exon in FN within vascular smooth muscle cells triggers phenotypic switching to a synthetic state and extracellular matrix remodeling through the ITGB1/FAK/Src/RUNX2 pathway. These changes ultimately reduce vascular mechanical strength and contribute to AVFA development. Furthermore, we identify the splicing factor SRSF5 as a key regulator of EDA inclusion and characterize its potential binding sites, providing potential therapeutic targets for AVFA prevention.