VPS45 is a Sec1/Munc18 (SM) family protein essential for endosomal trafficking and cell-surface receptor recycling 1. It orchestrates vesicle-mediated protein transport by promoting Rab5-to-Rab7 conversion at early endosomes, facilitating cargo delivery to lysosomes 1. VPS45 functions as a SNARE-interacting component of the FERARI tethering platform, coordinating membrane fusion with fission to direct cargo into recycling pathways 2. In hepatocellular carcinoma, VPS45 is amplified on chromosome 1 and promotes oncogenic progression by recycling β1 integrin to the cell membrane, activating FAK-AKT signaling 3. VPS45 mutations cause severe congenital neutropenia 5 (SCN5), an autosomal recessive disorder characterized by life-threatening neutropenia, primary myelofibrosis, platelet dysfunction, and bone marrow failure 4. The Thr224Asn mutation destabilizes VPS45 protein, impairing endosomal-lysosomal trafficking, causing α-granule depletion in platelets and absent lysosomes in fibroblasts 4. SCN5 patients exhibit defective granulocyte colony-stimulating factor receptor trafficking and accelerated neutrophil apoptosis 1. Loss of VPS45 is embryonic lethal in mice 1. iPSC-derived bone marrow organoids enable modeling of VPS45-deficient hematopoiesis 5, while hematopoietic stem cell transplantation offers a potential therapeutic approach for this rare, fatal condition 6.