PSD3 (pleckstrin and Sec7 domain containing 3) functions as a guanine nucleotide exchange factor (GEF) for ARF6 1, regulating vesicle-mediated transport and membrane dynamics. Its expression shows brain-specific localization, particularly in the prefrontal cortex, conferring regional specificity to ARF6 signaling 1. Genetically, PSD3 variants associate with metabolic and immune phenotypes. Common PSD3 polymorphisms correlate with obesity, type 2 diabetes, and HDL cholesterol levels 2. A loss-of-function variant (L186T) reduces fatty liver disease susceptibility 3, and PSD3 downregulation via antisense oligonucleotides protects against NASH in mouse models 3. Additionally, PSD3 represents a novel genetic risk locus for myositis with anti-Jo-1 autoantibodies 4. In cancer contexts, PSD3 demonstrates paradoxical functions. It promotes esophageal squamous cell carcinoma proliferation and invasion while inversely regulating PD-L1, suggesting immunomodulatory roles in tumor progression 5. Circular PSD3 transcripts enhance papillary thyroid cancer aggressiveness via miR-7-5p/METTL7B axis regulation 6. Behaviorally, PSD3 variants influence alcohol consumption; the minor allele of rs13265422 associates with increased drinking frequency and binge drinking in adolescents and alcohol dependence in adults 1, mediated through prefrontal cortex function during executive control tasks.