PLD2 (phospholipase D2) is a phospholipase enzyme that selectively hydrolyzes phosphatidylcholine to generate phosphatidic acid (PA) and choline 1. Unlike PLD1, PLD2 exhibits higher basal activity with minimal response to protein kinase C and small GTPases, though it can be regulated by calcium and specific PKC isoforms 12. The enzyme contains two conserved HKD motifs essential for catalysis and dimerization 1. PLD2 functions in multiple cellular processes including signal transduction through PA production, cytoskeletal regulation, and membrane trafficking 3. The enzyme interacts with various regulatory proteins including Grb2, Sos, and Rac2, and surprisingly also acts as a guanine nucleotide exchange factor (GEF) 3. Disease relevance includes roles in cancer progression, where PLD2 promotes stemness and chemoresistance in ovarian cancer through HIF-1α-mediated transcriptional activation under hypoxic conditions 4. PLD2 expression is elevated in hepatocellular carcinoma with early-stage fibrosis, suggesting potential as a therapeutic target 5. In inflammatory conditions, PLD2 contributes to psoriasis pathophysiology by regulating macrophage infiltration and cytokine production 6. Clinical significance lies in its potential as both a biomarker and therapeutic target across multiple disease contexts.