10,12-Tricosadiynoic acid is a highly selective and orally active inhibitor of acyl-CoA oxidase-1 (ACOX1), which can treat high-fat diet- or obesity-induced metabolic diseases by improving mitochondrial lipid and ROS metabolism.

10,12-Tricosadiynoic acid-CoA rapidly inhibits ACOX1 activity in a time- and concentration-dependent manner. The activity of ACOX1 decreases by nearly 95% after 5 min of incubation with 10 eq of 10,12-Tricosadiynoic acid-CoA. ACOX1 activity is inhibited only if free 10,12-Tricosadiynoic Acid is activated as the CoA thioester, the substrate form. The inhibition of ACOX1 by 10,12-Tricosadiynoic acid-CoA is irreversible. And the kinetics parameters KI and kinact are calculated to be 680 nm and 3.18/min, respectively.

Administration of 10,12-Tricosadiynoic acid (100 μg/kg; oral gavage; daily; for 8 weeks; male Wistar rats) enhances hepatic mitochondrial fatty acid oxidation (FAO) by activating the SIRT1-AMPK pathway and proliferator activator receptor α, while reducing hydrogen peroxide accumulation in high-fat diet-fed rats, leading to significant decreases in hepatic lipid and ROS contents, body weight gain, and serum triglyceride and insulin levels.

Animal Model: Male Wistar rats (210-230 g) fed with high-fat diet. Dosage: 100 μg/kg. Administration: Oral gavage; daily; for 8 weeks