THEM4 (thioesterase superfamily member 4) is a mitochondrial enzyme with acyl-CoA thioesterase activity towards medium and long-chain fatty acyl-CoA substrates (C14-C18), playing a role in fatty acid metabolism 1. The protein exhibits dual regulatory functions in the AKT signaling pathway, acting as both an inhibitor and activator depending on cellular context 2. In pancreatic cancer, THEM4 functions as a tumor suppressor by inhibiting AKT phosphorylation and is downregulated in cancer tissues 3. THEM4 can be released from mitochondria through CAMK2A-mediated mechanisms, affecting mitochondrial function and tumor progression 3. The gene contains functional regulatory variants, including rs13320, which acts as a cis-eQTL affecting THEM4 expression and glucose homeostasis, with the T allele associated with higher expression in adipose tissue 4. THEM4 serves as a target for vitamin D signaling, where 1,25(OH)2D upregulates THEM4 expression through a vitamin D-responsive element in its promoter, subsequently suppressing the AKT/NF-κB/COX-2 inflammatory pathway 5. The protein also interacts with CARD9 in cholangiocarcinoma, facilitating AKT and mTOR phosphorylation to promote cancer progression 6.