LIPA (lipase A, lysosomal acid type) encodes lysosomal acid lipase, a critical enzyme that catalyzes the hydrolysis of cholesteryl esters and triglycerides within lysosomes. The enzyme functions by degrading cholesteryl ester core lipids from endocytosed low-density lipoproteins to generate free fatty acids and cholesterol, and hydrolyzes triglycerides and diglycerides with preference for sn-1 or sn-3 positions 1. LIPA requires lysosomal digestion for proper activation of transcription factors like PPAR and LXR in macrophages during efferocytosis 1. Mechanistically, LIPA enhances lysosomal biogenesis and increases free fatty acid production to fuel mitochondrial fatty acid oxidation, promoting anti-inflammatory macrophage reprogramming 2. Disease relevance includes Wolman disease, caused by complete absence of functional LIPA due to genetic mutations, presenting with organomegaly, malabsorption, and adrenal calcifications that can mimic hemophagocytic lymphohistiocytosis 3. Clinically, LIPA represents a significant cardiovascular risk factor, as coronary artery disease-risk alleles increase LIPA expression specifically in monocytes/macrophages, leading to larger atherosclerotic lesions and altered macrophage function 4. Additionally, LIPA serves as a therapeutic target in solid tumors, where small molecule inhibitors induce endoplasmic reticulum stress independent of lipase activity 5.