PLD

Phospholipase D (PLD) is a phospholipid-hydrolyzing enzyme that primarily converts phosphatidylcholine into phosphatidic acid (PA) and choline, thereby generating a key lipid second messenger involved in cellular signaling networks^[1][2]. Mechanistically, PA produced by PLD regulates multiple biological processes, including vesicular trafficking, exocytosis, autophagy, cellular metabolism, and stress-responsive signaling pathways, and can further influence downstream effectors such as mTOR and Akt signaling cascades^[2][3]. Through these functions, PLD contributes to the control of cell migration, membrane dynamics, endocytosis, cytoskeletal remodeling, and secretory processes that are essential for normal cellular homeostasis^[1][4]. Disease relevance is supported by evidence linking altered PLD activity or expression to tumor growth, metastasis, neurodegeneration, thrombotic disorders, inflammation, diabetes, and other pathological conditions characterized by dysregulated signaling and membrane trafficking^[1][4]. Compared with related isoforms, mammalian PLD1 and PLD2 share conserved catalytic domains but differ in regulatory architecture, subcellular localization, and basal activity, with PLD1 containing a unique internal regulatory loop and requiring stronger activation by regulatory proteins, whereas PLD2 exhibits higher constitutive activity and distinct membrane-associated regulation^[1][5]. For experimental applications, the availability of isoform-selective small-molecule PLD inhibitors has enabled mechanistic dissection of PLD1- and PLD2-dependent signaling pathways and has strengthened the evaluation of PLD as a therapeutic target in cancer and other diseases^[1].