USP6NL (USP6 N-terminal like) functions as a GTPase-activating protein for RAB43, RAB5A, and RAB30, regulating endocytic trafficking and signal transduction. It controls receptor internalization by inhibiting EGFR endocytosis when complexed with EPS8, and mediates retrograde transport from endosomes to the Golgi apparatus, including Shiga toxin trafficking and Golgi structural integrity. Disease relevance has emerged across multiple pathologies. In Alzheimer's disease, USP6NL expression in microglia is associated with disease susceptibility 1, and USP6NL-linked genomic regions show altered 5-hydroxymethylcytosine patterns correlating with amyloid-β and tau pathology 2. USP6NL variants associate with Lewy body pathology in Alzheimer's brains 3. In cancer, USP6NL overexpression drives oncogenic pathways. In breast cancer, high USP6NL sustains chr10 AKT phosphorylation and GLUT1 stability, fueling aerobic glycolysis and worse prognosis 4. USP6NL depletion suppresses colorectal cancer progression by inducing CASP9-mediated apoptosis and inhibiting epithelial-mesenchymal transition 5. In glioblastoma, USP6NL promotes temozolomide resistance through EGFR signaling and reduced DNA damage repair 6. Additionally, USP6NL DNA methylation alterations regulated by MAGI2-AS3 suppress colorectal cancer via MYC translation modification 7. In osteoporosis, USP6NL upregulation in affected tissues suggests roles in oxidative stress and calcium homeostasis pathways 8. Collectively, USP6NL represents a multifunctional protein with therapeutic potential across neurodegenerative and malignant diseases.