PAFAH1B3 encodes the alpha1 catalytic subunit of cytosolic platelet-activating factor acetylhydrolase type I, a heterotetrameric enzyme that hydrolyzes the acetyl group at the sn-2 position of platelet-activating factor (PAF) and related lipid mediators [UniProt]. The protein functions as both homodimers and heterodimers with PAFAH1B2, with substrate specificity varying by subunit composition. PAFAH1B3 plays a critical developmental role in the brain, as demonstrated by a case of functional hemizygosity due to PAFAH1B3-CLK2 fusion causing mental retardation, ataxia, and brain atrophy 1. In cancer biology, PAFAH1B3 is substantially dysregulated. It is upregulated in pancreatic ductal adenocarcinoma, lung adenocarcinoma, and hepatocellular carcinoma, where high expression associates with poor prognosis and metastatic potential 234. PAFAH1B3 promotes cancer progression through epithelial-mesenchymal transition (EMT) and can exist in both chr19 and extrachromosomal circular DNA forms 53. Knockdown suppresses cell proliferation, invasion, and migration while modulating immune infiltration 6. Beyond cancer, PAFAH1B3 participates in endothelial cell function through insulin-regulated protein palmitoylation at cysteines 56 and 206, affecting angiogenesis and cell migration 7. Proteogenomic analysis identifies PAFAH1B3 as a potential mediator in Parkinson's disease pathogenesis 8. These findings position PAFAH1B3 as both a prognostic biomarker and therapeutic target across multiple diseases.