PLA2G4D is a calcium-dependent phospholipase A2 that catalyzes the hydrolysis of glycerophospholipids at the sn-2 position, with a preference for linoleic acid [UniProt]. Beyond canonical phospholipase activity, PLA2G4D mediates acyl-CoA-independent transacylation reactions, transferring fatty acids between phospholipids and acylglycerols to generate diacylglycerols and triacylglycerols 1. The enzyme is selectively expressed in stratified squamous epithelia, particularly keratinocytes, where proinflammatory cytokines strongly upregulate its expression 21. In keratinocytes, PLA2G4D loss-of-function produces complex lipidomic changes and alters transcriptional programs controlling cell proliferation, differentiation, and signaling 1. PLA2G4D has emerged as a key player in inflammatory skin diseases. It is dramatically upregulated in psoriatic epidermis compared to normal or atopic dermatitis skin, where lipids synthesized by PLA2G4D may serve as autoantigens driving autoreactive T-cell responses 23. In allergic dermatitis, PLA2G4D, along with CH25H and IFI6, was identified as a candidate diagnostic gene with positive correlations to abnormal immune activation, particularly Th17 cell immune responses 4. In prostate cancer, higher PLA2G4D expression correlated with lower PSA levels and favorable prognostic indicators 5. Recent evidence positions PLA2G4D as a component of lipid metabolism-related predictive models for cutaneous malignant melanoma progression 6, though its specific mechanistic contribution to oncologic outcomes remains incompletely defined.