GCDH (glutaryl-CoA dehydrogenase) is a mitochondrial enzyme that catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO2, a critical step in the degradation of lysine, hydroxylysine, and tryptophan 1. The enzyme uses electron transfer flavoprotein as its electron acceptor and localizes to the mitochondrial matrix 1. Beyond its classical metabolic role, GCDH functions in protein modification through crotonylation. In glioblastoma stem cells, GCDH accumulates crotonyl-CoA that translocates to the nucleus, where it interacts with the crotonyltransferase CBP to promote histone lysine crotonylation 2. Similarly, in hepatocellular carcinoma, GCDH-mediated crotonylation of glycolytic and pentose phosphate pathway proteins suppresses tumor progression by limiting the Warburg effect and inducing cellular senescence 3. In melanoma, GCDH suppresses cell death by controlling NRF2 glutarylation, preventing apoptotic signaling 4. Pathogenic GCDH variants cause glutaric aciduria type 1 (GA1), a rare autosomal recessive neurometabolic disorder characterized by accumulation of neurotoxic metabolites and striatal damage before age 3-6 years in untreated patients 1. Over 421 different GCDH variants have been identified, with variant pathogenicity correlating to residual enzyme activity 5. Early newborn screening and lysine-restricted diet substantially improve neurological outcomes 1, and AAV9-mediated GCDH gene therapy shows promise in preclinical models 6.