PLPP3 encodes lipid phosphate phosphatase 3 (LPP3), a membrane-bound enzyme that dephosphorylates bioactive lipids including lysophosphatidic acid (LPA) and sphingosine-1-phosphate 1. Primary function: PLPP3 terminates LPA signaling by converting it to receptor-inactive products, thereby regulating vascular cell behavior and inflammation 2. Mechanism: LPP3 localizes to endothelial cells, smooth muscle cells, and macrophages within atherosclerotic plaques, where it counteracts pro-inflammatory LPA signaling through LPA receptors 3. In vascular endothelium, PLPP3 is upregulated during oxidative stress and regulated by NF-κB transcription factors downstream of LPA signaling 4. Disease relevance: Genome-wide association studies identified PLPP3 variants associated with coronary artery disease susceptibility 5. Hepatic and systemic PLPP3 deletion worsens atherosclerosis in mice through altered plasma lipid composition, with smooth muscle cell LPP3 being particularly critical 65. Clinical significance: PLPP3 repression in atherosclerotic plaques correlates with increased cardiovascular event risk, suggesting PLPP3 dysfunction promotes atherogenesis 3. The LPA-LPP3 axis represents a novel therapeutic target orthogonal to traditional lipid-lowering approaches 2. Additionally, PLPP3 expression in endothelial cells promotes vascular repair after ischemic stroke 7.