ACAA1 encodes a peroxisomal thiolase that catalyzes the thiolytic cleavage of 3-oxoacyl-CoA intermediates of varying chain lengths, playing a central role in peroxisomal fatty acid β-oxidation. The enzyme cleaves straight-chain short, medium, long, and very long-chain acyl-CoA species and contributes to bile acid metabolism and long-chain polyunsaturated fatty acid biosynthesis. ACAA1 dysfunction has emerged as clinically significant across multiple malignancies and metabolic disorders. In triple-negative breast cancer, ACAA1 inhibition restrains proliferation and potentiates CDK4/6 inhibitor response; trimetazidine, an existing cardiac drug, reduces ACAA1 protein levels and enhances abemaciclib efficacy 1. In pancreatic ductal adenocarcinoma, ACAA1 knockout reduces mitochondrial ATP production and triggers protective autophagy, extending survival in preclinical models 2. ACAA1 is downregulated in non-small-cell lung cancer and head and neck squamous cell carcinoma, where low expression associates with favorable prognosis 34. Conversely, ACAA1 is upregulated in endometrial cancer, where it activates PI3K/AKT/Nrf2 signaling to suppress ferroptosis and drive tumor progression 5. Genetically, ACAA1(N392S) is a monogenic risk factor for Alzheimer disease; ACAA1 depletion impairs docosahexaenoic acid biosynthesis, suggesting early lipid dysregulation in neurodegeneration 6. Environmental exposure to polycyclic aromatic hydrocarbons suppresses PPARα/ACAA1 signaling and drives hepatic steatosis 7. ACAA1 has also been identified as a susceptibility gene in preeclampsia 8.