ARFGEF3 is a guanine nucleotide exchange factor implicated in metabolic regulation and cancer biology. In pancreatic islet cells, ARFGEF3 negatively regulates insulin and glucagon granule biogenesis, suggesting a role in glucose homeostasis. In breast cancer, ARFGEF3 functions as part of the BIG3-PHB2 complex, where it inhibits nuclear translocation of prohibitin 2 (PHB2) and enhances estrogen receptor alpha (ERα) transcriptional activity 1. Mechanistically, ARFGEF3 acts as an A-kinase anchoring protein that coordinates protein kinase A and protein phosphatase 1 signaling to modulate E2/ERα signaling in ERα-positive breast cancer cells 12. Clinically, ARFGEF3 shows relevance across multiple disease contexts. A genome-wide association study identified rs143276236 in ARFGEF3 as significantly associated with metformin glycemic response in African American patients with type 2 diabetes (P = 1.17 × 10⁻⁹), suggesting pharmacogenomic importance 3. ARFGEF3 has also been identified as a potential candidate gene in intellectual disability pathology 4 and as a biomarker candidate for glioblastoma subtype classification 5. Additionally, ARFGEF3 was found in interaction networks with known suicide behavior candidate genes in population studies 6. These findings indicate ARFGEF3's pleiotropic involvement in metabolic, oncologic, and psychiatric phenotypes.