ACADVL encodes very long-chain acyl-CoA dehydrogenase (VLCAD), a mitochondrial enzyme catalyzing the first rate-limiting step of fatty acid beta-oxidation 1. VLCAD specifically dehydrogenates saturated fatty acyl-CoA thioesters with 12-24 carbon chains, generating trans-2-enoyl-CoA and transferring electrons to electron transfer flavoprotein as the physiologic electron acceptor. This reaction initiates fatty acid catabolism for ATP production. ACAdvl mutations cause VLCAD deficiency, an autosomal recessive fatty acid oxidation disorder with phenotypic heterogeneity correlating strongly with genotype 1. Severe mutations eliminating enzyme activity cause early-onset childhood disease with cardiomyopathy and high mortality, while hypomorphic mutations permitting residual activity result in milder childhood presentations or adult-onset skeletal muscle disease with exercise-triggered rhabdomyolysis 1. Newborn screening identifies suspected VLCAD deficiency, though 57% of screen-positive individuals carry only single variants, highlighting diagnostic complexity 2. Clinically, VLCAD deficiency management requires specialized nutrition guidelines balancing fat intake and carbohydrate provision to prevent hypoketotic hypoglycemia and metabolic decompensation 3. Beyond primary deficiency, VLCAD downregulation in tumor-infiltrating CD8+ T cells impairs anti-tumor immunity by promoting long-chain fatty acid accumulation and lipotoxicity, suggesting ACADVL restoration as a potential immunotherapy strategy 4.