PNPLA8 encodes a calcium-independent phospholipase A2 that catalyzes the hydrolysis of phospholipids, playing critical roles in lipid metabolism, mitochondrial function, and neurodevelopment 1. The enzyme exhibits broad substrate specificity, hydrolyzing phosphatidylethanolamine, phosphatidylcholine, and phosphatidylinositol while preferentially producing 2-arachidonoyl lysophosphatidylcholine, a key metabolite in eicosanoid signaling 2. PNPLA8 is essential for maintaining mitochondrial membrane composition and bioenergetics through cardiolipin metabolism 3. In hepatic tissues, PNPLA8 regulates autophagy and lipid homeostasis via the SREBP-2/PNPLA8 axis, with overexpression reducing hepatic steatosis 4. The protein is crucial for human brain development, where loss of function reduces basal radial glial cells and upper-layer neurons in cerebral organoids, contributing to developmental microcephaly 1. Biallelic pathogenic variants cause a spectrum of mitochondrial diseases ranging from congenital microcephaly with epileptic encephalopathy to adult-onset cerebellar ataxia, with phenotype severity correlating with variant location and age of onset 56. In cancer, PNPLA8 overexpression drives phospholipid reprogramming that promotes proliferation and migration in triple-negative breast cancer through PI3K/Akt and MAPK signaling activation 2.