THEM5 (thioesterase superfamily member 5) is a mitochondrial acyl-CoA thioesterase that catalyzes hydrolysis of long-chain fatty acyl-CoA substrates, particularly unsaturated species like linoleoyl-CoA 1. As a member of the 'hotdog' fold enzyme superfamily within type II ACOTs, THEM5 adopts a classical homodimeric structure and maintains cellular lipid homeostasis by regulating free and activated fatty acid ratios 2. THEM5 plays a critical role in cardiolipin remodeling, the key phospholipid component of the inner mitochondrial membrane 1. Loss of THEM5 impairs mitochondrial function, including respiration and β-oxidation capacity, and causes dysregulation of lipid metabolism leading to fatty liver development, particularly under high-fat diet conditions 1. Beyond fatty acid metabolism, THEM5 exhibits broader clinical relevance: differential transcript usage of THEM5 has been identified in Parkinson's disease brains with predicted functional consequences 3, higher THEM5 expression associates with cisplatin-induced peripheral neuropathy in cancer survivors 4, and THEM5 appears in prognostic gene signatures for acute kidney transplant rejection 5 and glioblastoma outcome prediction 6. These findings establish THEM5 as essential for mitochondrial lipid homeostasis with pleiotropic implications in neurodegeneration and cancer biology.