HADHA (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha) is a mitochondrial enzyme catalyzing the final three reactions of beta-oxidation, the major pathway for long-chain fatty acid breakdown into acetyl-CoA 1. As the alpha subunit of the heterotetrameric trifunctional enzyme complex, HADHA exhibits 2,3-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activities 1. Beyond beta-oxidation, HADHA possesses cardiolipin acyltransferase activity, participating in cardiolipin remodeling—a critical mitochondrial phospholipid function 2. HADHA regulates cellular energy metabolism at multiple levels. It couples fatty acid oxidation to oxidative phosphorylation (OXPHOS), with HADHA expression increased under metabolic stress (galactose supplementation, high-fat diet) 3. HADHA-deficient cells show impaired respiratory complex assembly and OXPHOS dysfunction 3. The enzyme promotes ketone body (β-hydroxybutyrate) production, which suppresses hepatic gluconeogenesis by inhibiting HDAC7 activity 4. Disease relevance is substantial: mutations cause mitochondrial trifunctional protein deficiency and long-chain 3-hydroxyl-CoA dehydrogenase deficiency. HADHA dysregulation contributes to osteoarthritis through excessive fatty acid oxidation-driven SOX9 degradation 5 and intrahepatic cholangiocarcinoma chemoresistance via post-translational modifications affecting enzyme stability 6. HADHA regulation is also critical for effector T regulatory cell differentiation and immune tolerance 7.