ARHGEF15 (also known as Ephexin5) is a Rho-specific guanine nucleotide exchange factor (GEF) that activates RhoA and mediates VEGF-induced Cdc42 activation in endothelial cells 1. It does not activate RAC1 or CDC42 directly, though it can potentiate Cdc42 signaling in specific contexts 2. ARHGEF15 is highly enriched in developing endothelial cells and is essential for neonatal retinal vascularization and angiogenesis 31, functioning through regulation of actin polymerization and cell motility. Beyond vascular development, ARHGEF15 plays context-dependent roles in disease. In pancreatic ductal adenocarcinoma, ARHGEF15 overexpression promotes cancer cell motility and proliferation through Rho pathway activation, correlating with poor prognosis 2. In endothelial cells, ARHGEF15 promotes migration via STAT3 phosphorylation rather than proliferation 4. Conversely, ARHGEF15 functions as a developmental synapse repressor (Ephexin5); its pathological elevation in Alzheimer's disease drives amyloid-β-induced dendritic spine loss and cognitive impairment, and reducing its expression ameliorates disease-like phenotypes 5. ARHGEF15 has also been implicated in early-onset epilepsy, where mutations reduce GEF exchange activity 6, and upregulation occurs in alcohol use disorder brain tissue 7. These findings indicate ARHGEF15 represents a pleiotropic regulator with therapeutic potential across multiple disease contexts.