HSD17B4 is a bifunctional peroxisomal enzyme catalyzing two critical steps in fatty acid β-oxidation: hydration of 2-enoyl-CoA to 3-hydroxyacyl-CoA and subsequent dehydrogenation to 3-ketoacyl-CoA 1. The 80 kDa protein contains distinct functional domains: an N-terminal 32 kDa fragment performs dehydrogenase reactions on both steroids and acyl-CoA substrates, the central region (amino acids 324-596) catalyzes 2-enoyl-CoA hydratase activity, and the C-terminus facilitates lipid transfer between membranes 1. HSD17B4 processes straight-chain, branched-chain, and bile acid substrates, with highest expression in liver and kidney 1. Disease relevance includes HSD17B4 deficiency causing fatal Zellweger syndrome (D-bifunctional protein deficiency) 1 and mutations linked to syndromic primary ovarian insufficiency 2. Recent evidence demonstrates HSD17B4 deficiency impairs primary ciliogenesis, a ciliopathy-like phenotype rescuable by acetyl-CoA supplementation 3. In hepatocellular carcinoma, HSD17B4 regulates docosahexaenoic acid biosynthesis and ferroptosis sensitivity 4, while in prostate cancer, post-translational acetylation at K669 regulates HSD17B4 stability and cancer cell proliferation 5. These findings position HSD17B4 as both a metabolic enzyme critical for peroxisomal function and an emerging cancer therapeutic target.