STAMBP (STAM-binding protein) is a zinc metalloprotease that specifically cleaves Lys-63-linked polyubiquitin chains 1, functioning as a deubiquitinating enzyme critical for cellular homeostasis and signaling. Its primary role involves regulating cell surface receptor-mediated endocytosis and ubiquitin-dependent sorting to lysosomes, with endosomal localization required for efficient EGFR degradation 1. STAMBP potentiates bone morphogenetic protein signaling by antagonizing SMAD6/7 inhibition 2 and negatively regulates PI3K-AKT-mTOR and RAS-MAP signaling pathways 3. In cancer contexts, STAMBP promotes metastasis and chemotherapy resistance; elevated expression in breast and lung adenocarcinomas correlates with poor prognosis and predicts adverse outcomes 45. In pancreatic cancer, STAMBP enhances gemcitabine resistance by promoting the Warburg effect through the STAMBP-E2F1-PDK1 axis 6. Biallelic STAMBP mutations cause microcephaly-capillary malformation syndrome, characterized by progressive microcephaly, postnatal growth retardation, neuronal death in hippocampus and cortex, and ubiquitinated protein aggregation 7. AAV-mediated gene replacement therapy rescues these neurological defects in preclinical models, providing therapeutic potential 7. Additionally, STAMBP dysregulation associates with immune dysregulation in chr2 HIV-1 infection and serves as a validated biomarker in myasthenia gravis 89.