IQSEC1 is a guanine nucleotide exchange factor (GEF) that activates ARF GTPases (ARF1, ARF5, and ARF6) 12. Its catalytic activity is enhanced by lipid binding and operates at ER-plasma membrane contact sites 23. In neurons, IQSEC1 regulates vesicle-mediated endocytosis and dendritic spine development, mediating AMPAR receptor internalization during long-term depression 4. IQSEC1 controls focal adhesion disassembly through calcium-stimulated activation of ARF5, requiring interaction with the lipid transfer protein ORP3 3. In cancer biology, IQSEC1 acts as a molecular switch promoting invasion over growth via phosphoinositide metabolism regulation; elevated expression correlates with metastatic disease and poor prognosis 5. In bone metabolism, circular RNA derived from IQSEC1 promotes osteogenic differentiation of bone marrow mesenchymal stem cells through the miR-187-3p/Satb2 pathway 6. Disease-causing bi-allelic variants impair GEF function, resulting in intellectual disability, developmental delay, short stature, and dendritic spine dysgenesis 4. IQSEC1 polymorphisms associate with oral squamous cell carcinoma susceptibility and prognosis 7, while variants influence fasting C-peptide and insulin sensitivity during pregnancy 8.