LYPLA1 (lysophospholipase 1) functions primarily as an acyl-protein thioesterase that removes thioester-linked fatty acids from S-acylated cysteine residues in proteins 1. The enzyme exhibits dual catalytic activities, functioning both as a protein depalmitoylase and lysophospholipase, with significantly higher thioesterase activity 1. LYPLA1 catalyzes depalmitoylation of various substrate proteins including SQSTM1/p62, GPCPD1, and trimeric G proteins 23. The enzyme plays crucial regulatory roles in cellular processes by modulating protein palmitoylation status. In autophagy regulation, LYPLA1 negatively regulates the process by depalmitoylating SQSTM1, which decreases the affinity between SQSTM1 droplets and phagophore membranes 2. Under hypoxic conditions, LYPLA1 depalmitoylates GPCPD1, facilitating its relocalization to mitochondrial membranes and promoting mitophagy 3. LYPLA1 expression is regulated by testosterone through the miR-125a-5p pathway, and its dysregulation contributes to altered global protein palmitoylation levels in late-onset hypogonadism 4. In cancer contexts, LYPLA1 overexpression promotes cell proliferation and migration in non-small cell lung cancer, making it a potential therapeutic target 5. The enzyme works cooperatively with LYPLA2 to maintain cellular lipid homeostasis 6.