{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n AKR1C1 is a NADPH‐dependent aldo–keto reductase that plays a multifaceted role in both hormone metabolism and cellular detoxification. Functioning primarily as a 20α‐hydroxysteroid dehydrogenase, AKR1C1 catalyzes the conversion of progesterone to 20α–hydroxyprogesterone, thereby modulating local progesterone levels and influencing prereceptor hormone regulation in reproductive tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the context of endometrial and breast cancers, altered expression of AKR1C1 can shift the balance of active steroid hormones, potentially diminishing the protective effects of progesterone and contributing to tumor development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, AKR1C1 is subject to transcriptional regulation by the NRF2/KEAP1 pathway; its induction in response to oxidative stress and phase II inducers has been well documented, making it a useful biomarker for NRF2 activation in various cellular contexts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "6"}]}, {"type": "t", "text": " In several chemoresistant cancers, including colon and bladder carcinomas, up‐regulation of AKR1C1 contributes to resistance by detoxifying reactive aldehydes generated under oxidative stress, thereby promoting cell survival, proliferation, and invasion."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": " Furthermore, AKR1C1 is involved in the metabolism of synthetic steroids such as tibolone, where its catalytic activity determines the formation of specific hydroxytibolone metabolites that influence hormonal signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these studies underscore the pivotal role of AKR1C1 in integrating steroid hormone metabolism with cellular redox homeostasis and chemoresistance, highlighting its potential as both a biomarker and therapeutic target in various malignancies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jean-François Couture, Pierre Legrand, Line Cantin, et al. 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