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Abstract: retinopathy of prematurity (ROP) is a vision-threatening disorder that leads to pathological growth of the retinal vasculature due to hypoxia. Here, we investigated the potential effects of alamandine, a novel heptapeptide in the renin-angiotensin system, on hypoxia-induced retinal neovascularization and its underlying mechanisms. In vivo, the C57BL/6J mice with oxygen-induced retinopathy (OIR) were injected intravitreally with alamandine (1.0 μ M/kg per eye). In vitro, human retinal microvascular endothelial cells (HRMECs) were utilized to investigate the effects of alamandine (10 μ g/mL) on proliferation, apoptosis, migration, and tubular formation under vascular endothelial growth factor (VEGF) stimulation. Single-cell RNA sequencing (scRNA-seq) matrix data from GEO database and renin-angiotensin system (RAS)-related gene from the Molecular Signatures Database was sourced for subsequent analyses. By integrating scRNA-seq data across multiple species, we identified that RAS-associated endothelial cells populations were highly related to retinal neovascularization. The LC-MS/MS analysis revealed a significant decrease in alamandine levels in both the serum and retina of OIR mice when compared to the control group. Next, alamandine ameliorated hypoxia-induced retinal pathological neovascularization and physiologic revascularization in OIR mice. In vitro, alamandine effectively mitigated VEGF-induced proliferation, scratch-wound healing, and tube formation of HRMECs primarily by inhibiting the HIF-1 α/VEGF pathway. Further, coincubation with D-Pro⁷(Mas-related G protein-coupled receptor D (mrgD) antagonist) hindered the beneficial impacts of alamandine on hypoxia-induced pathological angiogenesis both in vivo and in vitro. Our findings suggested that alamandine could mitigate retinal neovascularization by targeting the mrgD-mediated HIF-1 α/VEGFA pathway, providing a potential therapeutic agent for OIR prevention and treatment.