PSD4 (pleckstrin and Sec7 domain containing 4) is a guanine nucleotide exchange factor (GEF) that activates ARF6 and ARL14 small GTPases, regulating vesicular trafficking and cytoskeletal dynamics. In dendritic cells, PSD4-mediated ARL14 activation controls MHC class II-containing vesicle movement along actin filaments, facilitating immune responses 1. PSD4 interacts with phosphatidylinositol phosphates and participates in membrane recycling processes essential for cellular homeostasis. In cancer contexts, PSD4 expression patterns correlate with disease progression and prognosis. High PSD4 expression promotes breast cancer brain metastases through ferroptotic resistance and vasculogenic mimicry 2, while DDR1-mediated PSD4 recruitment to ARF6 drives hepatocellular carcinoma metastasis 3. Conversely, in alcohol-related HCC, TNF-α/NF-κB signaling epigenetically suppresses PSD4 through promoter methylation; restoration of PSD4 expression inhibits pro-EMT CDC42 activity and reduces tumor progression 4. PSD4 expression is also regulated by ALKBH1-mediated DNA demethylation in metabolic dysfunction-associated steatotic liver disease, where PSD4 upregulation alleviates hepatic steatosis 5. These findings establish PSD4 as a context-dependent regulator of cancer progression and metabolic disease, with potential therapeutic significance as both a diagnostic marker and intervention target.