PLA2G5 encodes a secretory, calcium-dependent phospholipase A2 that hydrolyzes the sn-2 fatty acyl chains of extracellular phospholipids, preferentially releasing unsaturated fatty acids such as oleoyl and linoleoyl groups. In immune cells, PLA2G5 generates bioactive lipids—including lysophospholipids, fatty acids, and eicosanoids—that coordinate innate immunity. It promotes bacterial phagocytosis and killing in macrophages through cardiolipin hydrolysis and lysophosphatidylethanolamine production, amplifies cysteinyl leukotriene biosynthesis in neutrophils and eosinophils, and regulates M2 macrophage polarization by releasing unsaturated fatty acids from low-density lipoprotein that prevent inflammatory M1 activation 1. In IL-4-activated macrophages, PLA2G5 generates prostaglandin E2, which regulates transglutaminase-2 activity implicated in type-2 inflammation 2. Beyond immunity, PLA2G5 influences metabolic homeostasis; knockout studies in obesity models show it counteracts adipose tissue inflammation and insulin resistance 3. PLA2G5 variants associate with lipid metabolism and coronary artery disease risk in population studies 45, though a Mendelian randomization analysis found no causal relationship between PLA2G5 expression and coronary heart disease events 6. Rare variants have been identified in inherited retinal dystrophies 7. Varespladib methyl, a PLA2G5 inhibitor, has been developed as a potential therapeutic for atherosclerotic disease.