ECHS1 (enoyl-CoA hydratase, short chain 1) is a key mitochondrial enzyme that catalyzes the hydration of medium- and short-chain enoyl-CoA substrates in fatty acid β-oxidation and branched-chain amino acid metabolism 1. The enzyme converts trans-2-enoyl-CoA species to corresponding 3-hydroxyacyl-CoA species, with high specificity for crotonyl-CoA and moderate activity toward other substrates 1. ECHS1 plays crucial roles beyond metabolism, regulating histone crotonylation through crotonyl-CoA availability, which affects chr10 remodeling and gene expression 2. In cancer contexts, ECHS1 dysregulation promotes malignant behaviors including cell proliferation, metastasis, and drug resistance 1. ECHS1 deficiency causes severe mitochondrial dysfunction leading to Leigh syndrome, a neurodegenerative disorder with poor survival outcomes 3. The enzyme also influences cardiac function, where deficiency leads to cardiomyopathy through enhanced histone acetylation 4. In early embryonic development, ECHS1-mediated histone crotonylation facilitates zygotic genome activation 5. Therapeutically, ECHS1 represents a promising target, with interventions including dietary modifications and nicotinamide mononucleotide showing beneficial effects in experimental models 46.