HACD3 (3-hydroxyacyl-CoA dehydratase 3) catalyzes the third step of long-chain fatty acid elongation, adding two carbons per cycle to produce very long-chain fatty acids (VLCFAs) 1. This endoplasmic reticulum-bound enzyme converts 3-hydroxyacyl-CoA intermediates to trans-2,3-enoyl-CoA, generating VLCFA precursors for membrane lipids and lipid mediators 2. HACD3 interacts with fatty acid elongase ELOVL proteins and AdipoR2 to facilitate elongation and unsaturated fatty acid incorporation into phospholipids 3. Beyond canonical dehydratase function, HACD3 exhibits non-metabolic roles in disease progression. In non-small cell lung cancer (NSCLC), HACD3 promotes malignancy through direct interaction with MKK7/MAPK10, suppressing MAPK signaling independent of fatty acid metabolism 4. Similarly, in colorectal cancer, HACD3 possesses intrinsic protein kinase activity, phosphorylating CDK2 to stimulate tumorigenesis 5. HACD3 also stabilizes influenza A virus PB1 protein by competing with autophagy receptor p62, preventing autophagic degradation and promoting viral replication 6. Clinically, HACD3 dysregulation associates with metabolic dysfunction-associated steatohepatitis (MASLD), where reduced TCF7l2-mediated transcriptional repression elevates HACD3 expression and triglyceride production 7. These findings establish HACD3 as a multifunctional protein with metabolic and oncogenic roles relevant to diabetes, liver disease, and cancer therapeutics.