HACD4 (3-hydroxyacyl-CoA dehydratase 4) catalyzes the third step of the long-chain fatty acid elongation cycle in the endoplasmic reticulum, converting 3-hydroxyacyl-CoA intermediates to trans-2,3-enoyl-CoA and enabling the addition of two carbons per cycle to very long-chain fatty acids (VLCFAs) 1. This enzyme participates in producing VLCFAs of varied chain lengths that serve as precursors for membrane lipids and lipid mediators 2. While HACD1 and HACD2 demonstrate redundant activity across saturated and unsaturated fatty acid elongation pathways with HACD2 as the major contributor, HACD4 shows minimal enzymatic activity in these pathways 2. HACD4 has emerging disease relevance: genetic variants in the 9p21.3 region containing HACD4 associate with atherosclerosis susceptibility in males 3, and frameshift mutations occur in microsatellite instability-high colorectal cancers, suggesting potential tumor suppressor functions 4. Additionally, HACD4 expression correlates with contextual fear conditioning behavior in mouse models 5, and recurrent structural alterations affecting HACD4 appear in pediatric B-cell precursor acute lymphoblastic leukemia 6. These findings suggest HACD4 participates in both lipid homeostasis and disease pathophysiology, though functional mechanisms in non-lipid contexts require further investigation.