Hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4) (HSD17B4)

Hydroxysteroid 17-beta dehydrogenase 4 (HSD17B4), also known as multifunctional enzyme type 2 (MFE-2) or D-bifunctional protein (DBP), is a critical peroxisomal enzyme involved in the beta-oxidation of very long-chain fatty acids and the biosynthesis of bile acids (UniProt P51659). It is a unique multifunctional protein containing three distinct domains: an N-terminal 3-hydroxyacyl-CoA dehydrogenase, a central enoyl-CoA hydratase, and a C-terminal sterol carrier protein 2-like domain (MedlinePlus Genetics). Mutations in the HSD17B4 gene lead to D-bifunctional protein deficiency, a severe neurodegenerative disorder characterized by neonatal seizures, hypotonia, and progressive psychomotor delay, as well as Perrault syndrome (NIH/NCBI). In the context of oncology, HSD17B4 is frequently overexpressed in various malignancies, including prostate and colon cancers, where it is thought to promote tumor progression through metabolic reprogramming and modulation of steroid hormones (PMID: 28930456). While experimental inhibitors like cytisine-linked isoflavonoids (CLIFs) have been studied for their ability to target the enzyme's hydratase domain, there are currently no FDA-approved drugs specifically targeting HSD17B4, and systemic inhibition poses significant safety risks due to its essential role in lipid homeostasis (GeneCards).

Other names

Multifunctional enzyme type 2MFE-2D-bifunctional proteinDBPPeroxisomal multifunctional enzyme type 217-beta-hydroxysteroid dehydrogenase 417-beta-HSD 4Multifunctional protein 2MFP-2SDR8C1

Inhibition of the enoyl-CoA hydratase or 3-hydroxyacyl-CoA dehydrogenase domains to disrupt lipid metabolism or steroid signaling.