PLA2G4E in health and disease: Insights from omics and functional analyses

The phospholipase A₂ (PLA₂) enzyme superfamily has been extensively studied, but comprehensive reviews on cytosolic phospholipase A₂ group IVE (PLA2G4E) remain scarce, limiting our understanding of its role in lipid metabolism and disease. Our review synthesizes current findings on the human PLA2G4E gene and its murine ortholog Pla2g4e, drawing from multi-omics analyses and a range of functional studies. Pla2g4e exhibits distinct expression patterns across tissues, suggesting potential tissue-specific roles. In addition to its phospholipase activity, PLA2G4E exhibits N-acyltransferase activity and responds to calcium influx. Emerging evidence suggests possible involvement in metabolic disorders such as obesity and diabetes, particularly through effects on glucose uptake and insulin sensitivity. PLA2G4E has been implicated in the synthesis of N-acylethanolamines with potential effects on energy homeostasis, stress adaptation, neuronal signaling, pain perception, cognition, and motor coordination. Genomic and preliminary functional evidence further point to possible roles in immune regulation and neurobiology, with some associations reported in neurodegenerative diseases such as Alzheimer's disease. Comprehensive insights into the biological roles of PLA2G4E are essential for clarifying its enzymatic functions and potential involvement in disease mechanisms; however, further experimental and clinical studies are needed to substantiate these emerging associations and assess its therapeutic potential.