ARF6 is an ADP-ribosylation factor GTPase that functions as a molecular switch regulating endosomal trafficking and cytoskeletal dynamics. Mechanistically, ARF6 cycles between GDP-bound inactive and GTP-bound active states, controlled by guanine nucleotide exchange factors like IQSEC2 1. Activated ARF6-GTP regulates clathrin-mediated endocytosis, receptor trafficking, and actin polymerization 2, while also controlling selective activation of dynein or kinesin motors for autophagosome transport 3. ARF6 demonstrates significant disease relevance across multiple pathways. In cancer, ARF6 cooperates with KRAS and MYC mutations to promote malignancy through enhanced energy metabolism and immune evasion 4. The ARF6-AMAP1 pathway drives tumor invasion and metastasis in pancreatic cancer by regulating integrin dynamics and PD-L1 recycling 5. In esophageal squamous cell carcinoma, CD24-mediated ARF6 stabilization activates ERK signaling, promoting metastasis and chemoresistance 6. ARF6 also promotes bladder smooth muscle cell contraction and proliferation, with implications for overactive bladder pathology 7. Clinically, ARF6 dysfunction contributes to Parkinson's disease pathogenesis through disrupted autophagosome transport 3, and IQSEC2-mediated ARF6 activation regulates AMPA receptor dynamics implicated in autism spectrum disorders 1. ARF6 emerges as a therapeutic target across pulmonary hypertension, cancer, and neurological disorders.