LYPLA2 (lysophospholipase 2) is a versatile acyl-protein thioesterase that regulates cellular signaling through reversible protein depalmitoylation and lipid metabolism. The enzyme hydrolyzes fatty acids from S-acylated cysteine residues in key signaling proteins, including trimeric G proteins, STAT3, and various membrane-associated proteins 1. LYPLA2 plays a crucial role in inflammatory signaling by depalmitoylating phosphorylated STAT3, enabling its nuclear translocation and promoting TH17 cell differentiation 2. The enzyme also demonstrates lysophospholipase activity, hydrolyzing prostaglandin glycerol esters (PG-Gs) in the order PGD2-G > PGE2-G > PGF2α-G, and metabolizing 1-arachidonoylglycerol but not 2-arachidonoylglycerol 3. LYPLA2 cooperates with LYPLA1 to maintain cellular lipid homeostasis, with knockout studies showing that loss of both enzymes dramatically increases lysophospholipid levels and causes morphological changes 4. Clinically, LYPLA2 shows therapeutic relevance in inflammatory bowel disease, where its inhibition provides symptom relief 2, and its expression is upregulated in FOLFOX-responsive colorectal cancer patients 5. The enzyme's dual role in protein depalmitoylation and lipid metabolism positions it as a critical regulator of membrane dynamics and cellular signaling pathways.