ACAD8 encodes isobutyryl-CoA dehydrogenase, a mitochondrial matrix enzyme that catalyzes the first step of valine catabolism, converting isobutyryl-CoA to (2E)-2-methylpropenoyl-CoA 123. The enzyme also exhibits secondary activity toward 2-methylbutyryl-CoA 12. ACAD8 participates in broader branched-chain amino acid (BCAA) metabolism and lipid homeostasis 45. Loss-of-function mutations in ACAD8 cause isobutyryl-CoA dehydrogenase deficiency (IBDD), a rare autosomal recessive metabolic disorder characterized by elevated C4-acylcarnitine levels detectable through neonatal screening 67. Most IBDD patients have excellent long-term prognosis with normal development when monitored regularly, though rare cases with concurrent genetic variants may present severe phenotypes 68. Recent evidence suggests ACAD8 acts as a cuproptosis-related tumor suppressor in colorectal cancer, with reduced expression associated with metastatic disease and chemotherapy resistance 9. Experimentally, modulating ACAD8 activity affects metabolic flux through glycolysis and fatty acid synthesis in adipocytes 4, and blocking BCAA oxidation via ACAD8 inhibition improves survival in models of severe propionyl-CoA metabolism disorders 10.