VPS25 encodes a component of the ESCRT-II complex that is essential for endosomal protein sorting and multivesicular body formation 1. The protein is highly conserved across eukaryotic species and universally expressed in human tissues, indicating a fundamental role in cellular function 1. VPS25 functions in the endosomal sorting pathway by facilitating the degradation of ubiquitinated membrane receptors, with disruption leading to altered cell signaling 2. Loss of VPS25 function causes defective receptor downregulation, particularly affecting Notch signaling, which triggers non-autonomous cell proliferation and autonomous apoptosis 2. In development, VPS25 is critical for craniofacial morphogenesis, with hypomorphic mutations causing jaw hypoplasia, cleft palate, and other craniofacial anomalies through perturbation of NOTCH signaling 3. VPS25 has significant disease relevance in cancer, where it promotes tumor progression in head and neck squamous cell carcinoma by creating an immunosuppressive microenvironment and upregulating the PVR-TIGIT signaling axis 4. In glioma, VPS25 regulates cell cycle progression through JAK-STAT signaling and is associated with poor prognosis 5. Constitutional translocations involving VPS25 may predispose to myelodysplastic syndrome 6. These findings establish VPS25 as both a critical developmental regulator and potential therapeutic target in cancer.