HADHSC Inhibitors

Chemical inhibitors of hydroxyacyl-CoA dehydrogenase (HADHSC) function by interfering with the mitochondrial fatty acid oxidation pathway in which HADHSC is a key enzyme. Etomoxir and perhexiline target enzymes upstream of HADHSC, such as carnitine palmitoyltransferase 1 (CPT1) and carnitine O-palmitoyltransferase (CPT) respectively, which are essential for the transport of long-chain fatty acids into the mitochondria. By inhibiting these transporters, they reduce the availability of fatty acyl-CoA substrates necessary for HADHSC to perform its enzymatic role in β-oxidation. Oxfenicine acts similarly by inhibiting carnitine O-acetyltransferase, thereby reducing the levels of acetyl-CoA, a substrate in fatty acid oxidation, and indirectly limiting HADHSC's activity. Trimetazidine inhibits long-chain 3-ketoacyl CoA thiolase, which is involved in the final step of β-oxidation, effectively decreasing the production of substrates for HADHSC, contributing to its inhibition.

Additionally, metabolic modulators such as malonate can increase the NADH/NAD+ ratio by inhibiting succinate dehydrogenase in the tricarboxylic acid (TCA) cycle. This shift can inhibit HADHSC, which relies on the NAD+/NADH balance for its dehydrogenase activity. Mildronate reduces the biosynthesis of carnitine, impairing fatty acid transport into mitochondria, which indirectly decreases the activity of HADHSC. Ranolazine and metoprolol indirectly inhibit HADHSC by reducing the rate of fatty acid oxidation, while lovastatin indirectly affects the enzyme by lowering the production of intermediates for fatty acid synthesis. Fenofibrate activates PPARα, which can alter gene expression related to fatty acid metabolism, indirectly affecting the activity of HADHSC by reducing substrate availability. Lastly, diphenyleneiodonium and nicotinamide riboside interfere with electron transport and NAD+/NADH balance, which can lead to the functional inhibition of HADHSC through altered cofactor availability and product inhibition.