{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nHSD17B4 encodes a multifunctional peroxisomal enzyme, also known as D‐bifunctional protein, that plays a central role in the β‐oxidation of fatty acids and in steroid metabolism. Structural studies have revealed that key catalytic modules—including an N‐terminal dehydrogenase and a central hydratase domain as well as a sterol carrier protein–2–like (SCP‐2L) domain—create an architecture optimized for binding and processing a variety of fatty acyl substrates. Mutational and photoaffinity investigations have further delineated how substrate–protein interactions occur within a large hydrophobic cavity, thereby guiding efficient oxidation reactions. These mechanistic insights underscore the fundamental role of HSD17B4 in peroxisomal lipid handling and steroid conversion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAlterations in HSD17B4 function have been linked to a spectrum of developmental and peroxisomal disorders. Mutations that impair its enzymatic activities lead to D‐bifunctional protein deficiency, a condition marked in infancy by neurological deficits, hearing loss, and abnormal accumulation of branched and very‐long‐chain fatty acids. In addition, variants in HSD17B4 have been identified in patients with Perrault syndrome—with sensorineural hearing loss and primary ovarian insufficiency—as well as in cases of premature ovarian failure and other syndromic forms of hearing impairment. Together, these findings highlight the importance of intact HSD17B4 function for normal neurological, auditory, and gonadal development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its metabolic duties in normal physiology, HSD17B4 influences hormone balance in various cancers. Its activity in inactivating potent estrogens and androgens has been linked to tumor behavior in hormonally driven malignancies such as prostate, testicular, breast, and liver cancers. Elevated expression of HSD17B4 in prostate and liver tumors is associated with enhanced cell proliferation, likely through modulation of downstream signaling pathways—including STAT3 and cell cycle regulators—while post‐translational modifications (for example, acetylation at lysine 669) and interactions with proteins such as SIRT3 and CREBBP regulate its stability and subcellular localization. Moreover, genetic polymorphisms in HSD17B4 have been found to modify cancer risk and treatment responses, highlighting its potential as both a prognostic marker and therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "22"}]}, {"type": "t", "text": ""}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Kristian M Koski, Antti M Haapalainen, J Kalervo Hiltunen, et al. 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