OXCT1 (3-oxoacid CoA-transferase 1) is the rate-limiting enzyme catalyzing the first step of ketone body catabolism in extrahepatic tissues 1. It transfers coenzyme A from succinyl-CoA to acetoacetate, producing acetoacetyl-CoA, which is further metabolized to acetyl-CoA for ATP production via the citric acid cycle 1. The enzyme functions as a dimeric complex with asymmetric catalytic competence, forming transient anhydride intermediates 1. Beyond canonical ketolysis, OXCT1 exhibits moonlighting functions as a lysine succinyltransferase 2. In hepatocellular carcinoma (HCC), OXCT1-mediated succinylation of LACTB K284 inhibits its proteolytic activity, promoting tumor progression 2. SUCLA2-coupled OXCT1 activation enhances ketolysis and HCC cell proliferation; acetohydroxamic acid treatment inhibits this pathway 3. OXCT1 also regulates macrophage polarization—high expression in tumor-associated macrophages promotes CD8+ T-cell exhaustion via succinate-mediated epigenetic modifications, while inhibition enhances antitumor immunity 4. In triple-negative breast cancer, OXCT1 increases PGK1 protein stability through K146 succinylation, promoting aerobic glycolysis and immune escape 5. Clinically, OXCT1 dysregulation associates with multiple malignancies and metabolic disease. In diabetic cardiomyopathy, reduced OXCT1 expression impairs ketone utilization; empagliflozin restores expression and improves mitochondrial function 6. Conversely, in obesity-induced type 2 diabetes, elevated muscle OXCT1 contributes to hyperglycemia; pimozide (OXCT1 inhibitor) restores glucose oxidation 7. High OXCT1 expression in macrophages correlates with poor HCC prognosis 4, positioning OXCT1 as a potential biomarker and therapeutic target.