EHHADH is a peroxisomal trifunctional enzyme catalyzing critical steps in fatty acid beta-oxidation, including enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activities 1. It processes long-chain and branched-chain fatty acids through peroxisomal beta-oxidation and regulates medium-chain dicarboxylic fatty acid levels, which are essential regulators of all fatty acid oxidation pathways 2. EHHADH expression is positively regulated by acetylation during metabolic fuel availability, activating its oxidative function 1, and by PPARα signaling and its upstream regulator PPARGC1A 3. Clinically, EHHADH dysfunction is associated with Fanconi renotubular syndrome 3 and proximal tubular acidosis resulting from bicarbonate wasting 4. In cancer contexts, dysregulated EHHADH expression shows opposite patterns: elevated levels promote osteosarcoma and lung squamous cell carcinoma proliferation through altered lipid metabolism 52, while downregulation in hepatocellular carcinoma—associated with TP53 mutations and loss of VHL function—correlates with ferroptosis escape and hepatocyte dedifferentiation 67. In metabolic disease, EHHADH activation ameliorates diet-induced fatty liver through enhanced long-chain fatty acid oxidation 3.