SCG3 (secretogranin III) is a granin protein family member with dual roles in secretory granule biogenesis and pathological angiogenesis. Primary function: SCG3 regulates secretory granule biogenesis and acts as a sorting receptor for intragranular proteins including chr15 A 1. SCG3 promotes endothelial proliferation, migration, and tube formation through MEK/ERK signaling 2. Mechanism: Unlike pan-angiogenic factors, SCG3 exhibits disease-restricted angiogenic activity, with highest binding affinity to diabetic versus healthy retinal vasculature 3. SCG3 enhances vascular permeability by binding homologous receptors and induces Src phosphorylation in endothelial cells 4. Disease relevance: SCG3 is upregulated in diabetic retinopathy (DR), retinopathy of prematurity (ROP), and choroidal neovascularization, driving pathological neovascularization and vascular leakage 5. SCG3 elevation also associates with gastrointestinal symptoms in long COVID, suggesting brain-gut axis involvement 6. Clinical significance: SCG3-neutralizing antibodies effectively alleviate retinal vascular leakage and neovascularization in preclinical models with superior safety profiles compared to anti-VEGF agents; systemic anti-SCG3 therapy avoids systemic developmental toxicity seen with VEGF inhibitors 7. Humanized anti-SCG3 antibodies demonstrate potent therapeutic efficacy for DR treatment, with EBP3 hFab outperforming current aflibercept standards 8.