ATP13A3 is a P-type ATPase functioning as a polyamine transporter localized to recycling endosomes 1. It uses ATP energy to mediate polyamine uptake, particularly of putrescine, spermidine, and spermine, from endosomal compartments into the cytosol 12. In vascular endothelial cells, ATP13A3 maintains polyamine homeostasis critical for cell proliferation, survival under stress, and barrier function 1. Loss-of-function variants in ATP13A3 cause pulmonary arterial hypertension (PAH) with definitive evidence for gene-disease causality 3. PAH-associated variants impair polyamine transport, reducing endothelial polyamine content and causing EC dysfunction including reduced proliferation, increased apoptosis, and enhanced permeability 1. Heterozygous mice carrying disease-associated Atp13a3 variants spontaneously develop PAH with elevated pulmonary pressures and vascular remodeling 1. Beyond PAH, ATP13A3 regulates polyamine uptake in neuroblastoma cells, where high expression associates with poor survival and DFMO-induced polyamine uptake 4. High ATP13A3 expression in pancreatic cancer correlates with metastatic potential and decreased overall survival 2. These findings establish ATP13A3 as a critical regulator of cellular polyamine homeostasis with therapeutic implications for vascular and neoplastic diseases.