ECHDC3 is a mitochondrial enoyl-CoA hydratase involved in fatty acid metabolism and insulin sensitivity regulation. The gene contains conserved hydro-lyase domains and localizes to mitochondria where it participates in fatty acid metabolic processes 1. Mechanistically, ECHDC3 expression in adipose tissue is genetically regulated by cis-eQTL variants and directly impacts insulin sensitivity. ECHDC3 silencing in adipocytes significantly reduces insulin-stimulated glucose uptake and Akt phosphorylation, with downstream effects on γ-linolenate biosynthesis pathways and insulin resistance-associated genes 1. ECHDC3 expression correlates positively with the Matsuda insulin sensitivity index across African American and European populations 1. Clinical relevance spans multiple diseases. ECHDC3 variants associate with white matter hyperintensity and regulate right hippocampal microstructural integrity in type 2 diabetes patients, mediating effects on episodic memory decline 2. The rs7920721 variant represents a genome-wide significant Alzheimer's disease susceptibility locus, with altered ECHDC3 expression observed in AD brains compared to controls 3. In Alzheimer's disease progression, ECHDC3 expression negatively associates with structural brain atrophy in the thalamus, cerebellum, and frontal regions 4. Additionally, ECHDC3 upregulation correlates with coronary artery lesion progression and serves as a prognostic biomarker in kidney renal clear cell carcinoma 56.