{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n AKR1C4 is a member of the human aldo‐keto reductase family that plays a critical role in steroid hormone and bile acid metabolism. It catalyzes the NADPH‐dependent reduction of 3‑oxo groups on steroids—acting predominantly as a 3α‐hydroxysteroid dehydrogenase—to inactivate potent hormonal ligands and facilitate bile acid synthesis. In hepatic tissue, AKR1C4 is the major enzyme responsible for converting 5β‑dihydrosteroids (for example, testosterone metabolites) into less active 5β‑tetrahydrosteroids, and it efficiently metabolizes both free and conjugated steroids as well as synthetic agents such as tibolone and exemestane, thereby contributing to pre‐receptor regulation of hormone activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the context of developmental steroidogenesis, mutations in AKR1C4 (in conjunction with AKR1C2) have been implicated in impairing the “backdoor” pathway for dihydrotestosterone synthesis in the fetal testis, illustrating its importance in sexual differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, compared to its related isoforms, AKR1C4 demonstrates superior catalytic efficiency that is less affected by steroid conjugation, underscoring its central role in metabolizing a variety of steroid substrates."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Functional polymorphisms in AKR1C4 have been associated with alterations in enzyme activity, which may in turn influence progesterone metabolism and neurosteroid levels, potentially contributing to mood-related phenotypes in humans."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, transcriptional regulation of AKR1C4 by nuclear receptors such as liver X receptor α links its expression to cholesterol homeostasis and bile acid biosynthesis, positioning this enzyme as a key mediator at the crossroads of steroid inactivation and lipid metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Together, these studies establish AKR1C4 as a pivotal enzyme in the inactivation of steroid hormones and the synthesis of bile acids—with implications for normal development, endocrine regulation, and the metabolism of therapeutic agents.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Tea Lanišnik Rižner, Trevor M Penning "}, {"type": "b", "children": [{"type": "t", "text": "Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Steroids (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.steroids.2013.10.012"}], "href": "https://doi.org/10.1016/j.steroids.2013.10.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24189185"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24189185"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Stephan Steckelbroeck, Yi Jin, Busola Oyesanmi, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Stereospecific reduction of 5β-reduced steroids by human ketosteroid reductases of the AKR (aldo-keto reductase) superfamily: role of AKR1C1-AKR1C4 in the metabolism of testosterone and progesterone via the 5β-reductase pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20101804"}], "href": "https://doi.org/10.1042/BJ20101804"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21521174"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21521174"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Amity Platt, Zuping Xia, Ying Liu, et al. 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