HACD2 (3-hydroxyacyl-CoA dehydratase 2) catalyzes the dehydration step of very long-chain fatty acid (VLCFA) elongation in the endoplasmic reticulum, converting 3-hydroxyacyl-CoA intermediates to trans-2,3-enoyl-CoA 1. HACD1 and HACD2 exhibit functional redundancy as the major 3-hydroxyacyl-CoA dehydratases, participating in saturated and polyunsaturated FA elongation pathways, with HACD2 being the predominant enzyme 2. HACD2 forms a stable complex with trans-2-enoyl-CoA reductase (TECR) to facilitate substrate transfer during VLCFA synthesis 1. Beyond canonical lipid metabolism, HACD2 exhibits non-enzymatic functions in cancer progression. In pancreatic cancer, HACD2 promotes cell proliferation in a dehydratase-independent manner by binding parkin (PRKN) and enhancing PKM2 dissociation, reducing PKM2 ubiquitination and increasing dimerization to promote c-Myc expression 3. HACD2 has been identified as a dysplasia-associated gene with malignant transformation potential in oral squamous cell carcinoma 4 and as a prognostic gene in hepatocellular carcinoma risk models 5. Additionally, baseline HACD2 expression in white adipose tissue is lower in women with long-term weight loss, linking it to metabolic regulation and obesity 6. A locus near HACD2 associates with habitual sleep duration across multiple ancestry populations 7.