{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n AKR1C3, also known as type 5 17β‐hydroxysteroid dehydrogenase, is a multifunctional enzyme that plays a central role in steroid hormone metabolism, prodrug activation, and xenobiotic processing in cancer. In prostate tissue, AKR1C3 catalyzes the conversion of weak androgen precursors (such as Δ4‐androstene‐3,17‐dione) to testosterone and contributes to the metabolism of dihydrotestosterone, thereby sustaining androgen receptor signaling even when circulating androgen levels are low. This intracrine synthesis of androgens has been linked to the development of castration‐resistant prostate cancer (CRPC) and to resistance to antiandrogen therapies such as enzalutamide."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its role in prostate cancer, aberrant expression of AKR1C3 in breast and endometrial tumors alters the local balance of active estrogens and progesterone. By favoring the formation of active estrogenic compounds and reducing progesterone inactivation, AKR1C3 contributes to a pro‐estrogenic state that promotes tumor cell proliferation and may enhance metastasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, AKR1C3 has been identified as an aerobic nitroreductase capable of bioactivating hypoxia‐activated prodrugs, an activity that is subject to regulation by oxidative stress pathways such as the NRF2–ARE system."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Genetic polymorphisms in AKR1C3 have also been linked to increased risk for polycyclic aromatic hydrocarbon (PAH)–induced carcinogenesis, highlighting its role in modulating redox balance and mediating oxidative DNA damage in lung and hematologic malignancies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore the multifaceted functions of AKR1C3 as a key regulator of intracrine steroidogenesis, a modulator of drug resistance via prodrug activation, and a contributor to carcinogen bioactivation. Its central role in controlling hormone balance and promoting tumor progression across several cancer types positions AKR1C3 as a promising biomarker and therapeutic target in personalized oncology.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Changmeng Cai, Sen Chen, Patrick Ng, et al. 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