{"gene":"AKR1C3","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2001,"finding":"Recombinant AKR1C3 expressed in E. coli functions as a 3-keto-, 17-keto- and 20-ketosteroid reductase and as a 3α-, 17β- and 20α-hydroxysteroid oxidase in vitro, reducing 5α-DHT, androstenedione, estrone and progesterone to produce 3α-androstanediol, testosterone, 17β-estradiol and 20α-hydroxyprogesterone respectively; kinetic analysis (kcat/Km) showed preference for 5α-dihydrotestosterone and 5α-androstane-3,17-dione as substrates.","method":"In vitro enzymatic assay with homogeneous recombinant protein expressed in E. coli; kinetic analysis (kcat/Km); RT-PCR for tissue distribution","journal":"Molecular and cellular endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution with recombinant enzyme, multiple substrate assays with kinetic parameters, replicated across multiple steroid substrates","pmids":["11165022"],"is_preprint":false},{"year":2006,"finding":"Crystal structure of prostaglandin F synthase (AKR1C3/PGFS) containing NADPH and bimatoprost at 2.0 Å resolution revealed the PGD2 binding site and proposed catalytic mechanism: PGF2α formation from PGH2 involves direct hydride transfer from bound NADPH to the 9,11-endoperoxide of PGH2 without participation of specific amino acid residues; bimatoprost binds near the PGD2 site with reversed chain orientation.","method":"X-ray crystallography (2.0 Å resolution), inhibition assays, model building","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure at 2.0 Å with functional inhibition data and mechanistic model building","pmids":["16475787"],"is_preprint":false},{"year":2008,"finding":"AKR1C3 converts PGD2 to 9α,11β-PGF2α via 11-ketoprostaglandin reductase activity; overexpression of AKR1C3 in PC-3 prostate cancer cells elevated cell proliferation in response to PGD2 stimulation; this proliferative signaling was mediated through the FP (prostaglandin F) receptor and downstream PI3K/Akt pathway.","method":"Stable transfection of PC-3 cells with AKR1C3 cDNA; cell proliferation assays; FP receptor antagonist (AL8810); PI3K inhibitor (LY294002); Western blot for Akt phosphorylation","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — stable overexpression with pharmacological pathway dissection, single lab, two orthogonal approaches (receptor antagonist + kinase inhibitor)","pmids":["18508192"],"is_preprint":false},{"year":2009,"finding":"AKR1C3 is expressed in human adrenal zona reticularis and mediates adrenal testosterone production: siRNA knockdown of AKR1C3 in H295R adrenal cells significantly inhibited testosterone production, and ACTH stimulation increased adrenal vein testosterone levels in vivo.","method":"siRNA knockdown in H295R cells; testosterone measurement; adrenal vein sampling with ACTH stimulation; microarray, RT-PCR, immunohistochemistry","journal":"The Journal of clinical endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — siRNA loss-of-function with defined biochemical readout (testosterone production), orthogonal in vivo validation (adrenal vein sampling), replicated across multiple methods","pmids":["19336506"],"is_preprint":false},{"year":2012,"finding":"Crystal structures of AKR1C3 in complex with NADP+ and two inhibitor compounds (an N-(aryl)amino-benzoate and a bifunctional inhibitor/AR antagonist) revealed that inhibitors bind in the androstenedione-binding site; one compound forms a unique 'double-decker' structure; a phenylamino ring projecting into a subpocket confers selectivity over AKR1C1/AKR1C2.","method":"X-ray crystallography of AKR1C3·NADP+·inhibitor complexes; enzymatic inhibition assays; AR reporter gene assays; Western blot","journal":"Bioorganic & medicinal chemistry letters","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures with functional inhibition data and cell-based validation, single lab but multiple orthogonal methods","pmids":["22507964"],"is_preprint":false},{"year":2013,"finding":"AKR1C3 acts as a novel androgen receptor (AR)-selective enzymatic coactivator: it physically interacts with AR (demonstrated by co-immunoprecipitation), co-localizes with AR in prostate cancer cells and xenografts, is recruited to the promoter of an androgen-responsive gene (ChIP), and its coactivator function promotes prostate cancer cell and xenograft growth independently of its steroidogenic activity.","method":"Co-immunoprecipitation; chromatin immunoprecipitation (ChIP); confocal microscopy; stable transfection; xenograft growth assays; AR transactivation reporter assays; selective AKR1C3 inhibitor treatment","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, ChIP, co-localization, and functional xenograft studies; multiple orthogonal methods","pmids":["23995860"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of AKR1C3·NADP+·2'-des-methyl-indomethacin complex revealed a unique inhibitor binding mode, enabling rational design of indomethacin analogues with nanomolar potency, >100-fold selectivity over AKR1C1/AKR1C2, and blocking of testosterone formation in LNCaP-AKR1C3 cells.","method":"X-ray crystallography; enzymatic inhibition assays; cell-based testosterone formation assay","journal":"Journal of medicinal chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with functional enzyme inhibition assays and cell-based validation, single lab with multiple orthogonal methods","pmids":["23432095"],"is_preprint":false},{"year":2015,"finding":"AKR1C3 mediates resistance to enzalutamide in prostate cancer through intracrine androgen synthesis: shRNA knockdown or indomethacin inhibition of AKR1C3 resensitized enzalutamide-resistant cells to enzalutamide both in vitro and in vivo; overexpression of AKR1C3 was sufficient to confer resistance; LC/MS analysis confirmed elevated androgen precursors and androgens in resistant cells.","method":"shRNA knockdown; AKR1C3 overexpression; global gene expression analysis; LC/MS metabolite analysis; in vitro and in vivo (xenograft) drug sensitivity assays; indomethacin inhibition","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic manipulation (KD and OE), orthogonal pharmacological validation, metabolite quantification, both in vitro and in vivo readouts","pmids":["25649766"],"is_preprint":false},{"year":2015,"finding":"ERG (from TMPRSS2-ERG fusion) directly binds the AKR1C3 gene and regulates its expression; ERG knockdown reduced AKR1C3 expression, decreased DHT synthesis from 5α-androstanedione, and reduced PSA expression in VCaP cells, establishing an ERG/AKR1C3/AR feed-forward loop in prostate cancer.","method":"Lentivirus-mediated ERG knockdown; ChIP-seq (ERG binding to AKR1C3 gene); LC-MS androgen quantitation; gene expression analysis; immunohistochemistry","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP-seq for direct binding, loss-of-function with defined biochemical (DHT, PSA) readouts, multiple orthogonal methods","pmids":["25754347"],"is_preprint":false},{"year":2015,"finding":"AKR1C3 stabilizes the ubiquitin ligase Siah2 by physically binding to Siah2 and inhibiting its self-ubiquitination and degradation, thereby enhancing Siah2-dependent AR transcriptional activity in prostate cancer cells; both wild-type and catalytically inactive AKR1C3 partially rescued AR activity and growth defects in Siah2 knockdown cells, indicating a non-enzymatic role.","method":"Co-immunoprecipitation (AKR1C3-Siah2 interaction); Siah2 knockdown with re-expression of WT and catalytically inactive AKR1C3; ubiquitination assays; in vitro and orthotopic tumor growth assays; androgen level measurement","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP demonstrating direct binding, ubiquitination assay, catalytically inactive mutant rescue distinguishing enzymatic from non-enzymatic roles, in vivo validation","pmids":["26160177"],"is_preprint":false},{"year":2015,"finding":"Insulin upregulates AKR1C3 expression and activity in subcutaneous adipocytes in vitro, driving increased testosterone generation from androstenedione; in vivo DHEA challenge in women with insulin receptor mutations showed elevated testosterone production correlating with AKR1C3 induction.","method":"In vitro insulin treatment of differentiated adipocytes; AKR1C3 expression by real-time PCR; androgen measurement by LC-MS/MS; in vivo DHEA challenge with serial blood androgen measurement","journal":"Lancet","confidence":"High","confidence_rationale":"Tier 2 / Strong — orthogonal in vitro and in vivo experiments, quantitative hormone measurements, replicated across multiple subject groups","pmids":["26312838"],"is_preprint":false},{"year":2016,"finding":"AKR1C3 activation is a critical mechanism of resistance to abiraterone: overexpression of AKR1C3 conferred abiraterone resistance while downregulation resensitized resistant cells; AKR1C3 increases intracrine androgen synthesis and enhances AR transcriptional activity in abiraterone-resistant cells; indomethacin treatment overcame resistance both in vitro and in vivo.","method":"AKR1C3 overexpression and shRNA knockdown; intracrine androgen measurement; AR transcriptional activity assays; in vitro and in vivo (xenograft) drug sensitivity assays; indomethacin treatment","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic manipulation, androgen quantification, AR functional readout, both in vitro and in vivo validation","pmids":["27794047"],"is_preprint":false},{"year":2019,"finding":"AKR1C3 increases AR-V7 protein stability in enzalutamide-resistant prostate cancer cells through the ubiquitin-mediated proteasome pathway; the AKR1C3/AR-V7 complex collaboratively confers resistance to AR-targeted therapies; indomethacin targeting AKR1C3 decreases AR/AR-V7 protein expression both in vitro and in vivo.","method":"Co-immunoprecipitation (AKR1C3-AR-V7 interaction); proteasome pathway analysis; indomethacin treatment; Western blot; bioinformatic pathway analysis; in vivo xenograft studies","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct interaction, proteasome pathway analysis, pharmacological inhibition with in vivo validation","pmids":["31308078"],"is_preprint":false},{"year":2020,"finding":"AKR1C3 promotes HCC cell proliferation and metastasis by activating NF-κB signaling through modulation of TRAF6 and inducing its autoubiquitination; activated NF-κB releases proinflammatory factors that phosphorylate STAT3; STAT3 directly binds the AKR1C3 promoter and increases AKR1C3 transcription, forming a positive feedback loop; AKR1C3/NF-κB/STAT3 axis was validated by gain- and loss-of-function experiments.","method":"Gain- and loss-of-function experiments (overexpression and knockdown); NF-κB reporter assays; TRAF6 ubiquitination assays; STAT3 ChIP on AKR1C3 promoter; in vitro and in vivo (xenograft) proliferation and invasion assays; AKR1C3 inhibitor treatment","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional genetic manipulation, promoter ChIP, ubiquitination assay, orthogonal in vitro and in vivo validation","pmids":["33361392"],"is_preprint":false},{"year":2020,"finding":"The AKR1C3/AR-V7 axis confers cross-resistance to enzalutamide, abiraterone, apalutamide, and darolutamide; knockdown of AR-V7 resensitized enzalutamide-resistant cells to apalutamide and darolutamide; targeting AKR1C3 resensitized resistant cells through AR-V7 inhibition.","method":"shRNA knockdown of AR-V7 and AKR1C3; drug sensitivity assays; gene expression analysis","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis with shRNA knockdowns defining pathway order (AKR1C3→AR-V7→resistance), single lab","pmids":["32430485"],"is_preprint":false},{"year":2020,"finding":"AKR1C3/AR-V7 complex maintains CRPC tumor growth by repressing B4GALT1 (a tumor suppressor gene) expression; AKR1C3 interacts with AR-V7 protein in CRPC cells and reciprocally inhibits AR-V7 and AKR1C3 protein degradation.","method":"Co-immunoprecipitation; immunohistochemistry in clinical specimens; in vitro and in vivo (xenograft) tumor growth assays; B4GALT1 expression analysis","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for direct interaction, in vivo validation, single lab","pmids":["32902124"],"is_preprint":false},{"year":2021,"finding":"AHR (aryl hydrocarbon receptor) transcriptionally activates AKR1C3 expression in triple-negative breast cancer cells: AhR knockout decreased AKR1C3 expression; AhR enhanced AKR1C3 promoter reporter activity; reduced AKR1C3 enhanced doxorubicin sensitivity, linking AhR→AKR1C3→doxorubicin resistance.","method":"AhR CRISPR/Cas9 knockout; AKR1C3 promoter reporter assay; AKR1C3 siRNA knockdown; cell viability assays with doxorubicin; Western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assay for direct transcriptional regulation, genetic KO and KD with defined functional readouts, single lab","pmids":["31253396"],"is_preprint":false},{"year":2021,"finding":"PAH exposure (benzo[a]pyrene) induces AKR1C3 expression and 11-ketoreduction of prostaglandin D2 through an EGFR-dependent pathway: B[a]P causes c-Src-mediated EGFR phosphorylation and auto/paracrine EGFR activation; EGFR inhibition blocks B[a]P-induced AKR1C3 upregulation; DLCs (PCB126) block EGFR activation by binding its extracellular domain, explaining differential AHR ligand responses.","method":"EGFR inhibition; receptor binding and internalization assays; mutational amino acid exchange; docking analyses; nanopore long-read RNA-seq; kinase inhibitor studies","journal":"Environment international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutational analysis, receptor binding assays, pharmacological inhibition, single lab with multiple orthogonal methods","pmids":["34991250"],"is_preprint":false},{"year":2022,"finding":"AKR1C3-dependent lipid droplet (LD) formation is required for sorafenib resistance in HCC: CRISPR/Cas9 knockout of AKR1C3 fully depletes LD contents and redirects FA flux to phospholipids, sphingolipids, and mitochondria; AKR1C3-dependent LD accumulation protects cells from sorafenib-induced mitochondrial lipotoxicity; pharmacological inhibition of AKR1C3 induces autophagy-dependent LD catabolism, mitochondrial fission, and apoptosis.","method":"CRISPR/Cas9 gene editing; isotopic tracing with deuterium-labeled palmitate and 13C-labeled glucose; proteomics and metabolomics; Seahorse metabolic flux analysis; immunoblotting; immunofluorescence; AKR1C3 inhibitor treatment","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — CRISPR/Cas9 genetic manipulation, isotopic tracing, multi-omics, and functional metabolic assays with multiple orthogonal methods","pmids":["36451864"],"is_preprint":false},{"year":2022,"finding":"NRF2/MAFG transcription factor heterodimer directly binds the AKR1C3 promoter to activate its transcription; AKR1C3 in turn stabilizes PARP1 by decreasing its ubiquitination, promoting HCC cell proliferation; both catalytic and non-catalytic AKR1C3 functions drive tumor growth.","method":"ChIP (NRF2/MAFG binding to AKR1C3 promoter); AKR1C3 WT and catalytic mutant overexpression; PARP1 ubiquitination assay; in vitro and in vivo xenograft assays; AKR1C3 shRNA intratumoral injection","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — ChIP for direct promoter binding, ubiquitination assay, WT vs. catalytic mutant comparison revealing non-enzymatic role, in vivo validation","pmids":["35773412"],"is_preprint":false},{"year":2022,"finding":"Insulin-induced AKR1C3 in PCOS adipocytes converts both classical (androstenedione→testosterone) and 11-oxygenated androgens (11K-4AD→11K-T; 11K-5AD→11K-DHT) to potent androgens; conversion of 11-oxygenated androgens was kinetically superior to classical androgen formation by recombinant AKR1C3; 11K-T formed in adipocytes is subsequently inactivated by HSD11B1.","method":"HPLC discontinuous kinetic assays with recombinant AKR1C3; stable isotope dilution LC-HRMS quantitation of androgens in insulin-treated SGBS adipocytes; AKR1C3-deficient cell experiments","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with recombinant enzyme plus cell-based isotope tracing, multiple substrates characterized kinetically","pmids":["35560164"],"is_preprint":false},{"year":2023,"finding":"AKR1C3 suppresses ferroptosis in HCC through YAP/SLC7A11 signaling: AKR1C3 knockdown decreased YAP nuclear translocation, inhibited cystine transporter SLC7A11, increased intracellular ferrous iron, and induced ferroptosis; overexpression of AKR1C3 protected against ferroptosis.","method":"AKR1C3 knockdown and overexpression; YAP nuclear localization assay; SLC7A11 expression analysis; ferrous iron measurement; ferroptosis inducer sensitivity assays in vitro and in vivo","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional genetic manipulation with defined pathway (YAP→SLC7A11) mechanistic dissection, single lab","pmids":["36920042"],"is_preprint":false},{"year":2023,"finding":"AKR1C3 stabilizes AR in a non-enzymatic manner to induce FASN (fatty acid synthase) in PCOS adipocytes: insulin-induced AKR1C3 activates FASN through a PI3K/AKT/mTOR/NRF2 pathway in an AKR1C3- and AR-dependent manner; AKR1C3 interacts with AR (Co-IP, proximity ligation assay), co-occupies the FASN locus (ChIP-qPCR), and stabilizes AR from degradation; bifunctional but not monofunctional AKR1C3 inhibitors blocked FASN induction and lipid droplet formation.","method":"Co-immunoprecipitation; proximity ligation assay; ChIP-qPCR (AKR1C3 and AR co-occupancy at FASN promoter); pharmacological inhibition (PI3K/AKT/mTOR/NRF2 pathway); monofunctional vs. bifunctional inhibitor comparison; insulin treatment of SGBS adipocytes","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, PLA, ChIP-qPCR) demonstrating direct AKR1C3-AR interaction at target locus, pharmacological dissection of enzymatic vs. non-enzymatic roles","pmids":["36799021"],"is_preprint":false},{"year":2023,"finding":"Full-length androgen receptor (AR-FL) reciprocally regulates AKR1C3 expression by binding to a distal enhancer region of the AKR1C3 gene; PTUPB, a novel dual inhibitor, suppresses AKR1C3 activity more effectively than indomethacin or celecoxib, and synergizes with enzalutamide to suppress CRPC tumor growth by blocking AR/AR-V7 signaling.","method":"AR ChIP on AKR1C3 distal enhancer; AKR1C3 enzymatic activity assays; VCaP xenograft and patient-derived xenograft organoid experiments; combination drug treatment","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct AR binding to AKR1C3 enhancer, functional in vivo validation, single lab","pmids":["36596844"],"is_preprint":false},{"year":2012,"finding":"Activin A induces AKR1C3 expression and enzymatic activity (testosterone synthesis) in prostate cancer LNCaP and VCaP cells; inhibition of endogenous activin A in PC-3 cells decreased AKR1C3 levels and testosterone synthesis; androgens in turn suppress INHBA (activin A subunit) expression, forming a regulatory feedback.","method":"Activin A treatment and antagonist inhibition in prostate cancer cell lines and xenograft models; RT-PCR and protein expression; testosterone measurement; PC xenograft gene expression analysis","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional modulation of activin A with defined biochemical readouts, validated in multiple cell lines and xenograft models","pmids":["23024260"],"is_preprint":false},{"year":2018,"finding":"AKR1C3 promotes prostate cancer metastasis by activating ERK signaling to drive epithelial-mesenchymal transition (EMT): knockdown of AKR1C3 or inhibition of its enzymatic activity suppressed cell migration/invasion, increased E-cadherin, decreased vimentin, and downregulated ERK phosphorylation and EMT transcription factors (ZEB1, TWIST1, SLUG) in vitro; AKR1C3 knockdown also reversed EMT and suppressed tumor growth in xenografts.","method":"shRNA knockdown of AKR1C3; chemical inhibitor treatment; wound healing and Transwell invasion assays; Western blot for EMT markers and phospho-ERK; subcutaneous xenograft experiments; IHC on clinical specimens","journal":"Urologic oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological inhibition with defined pathway (ERK→EMT) and in vivo validation, single lab","pmids":["30139661"],"is_preprint":false},{"year":2015,"finding":"AKR1C3 is the critical enzyme activating the nitrogen mustard prodrug PR-104A: overexpression of AKR1C3 in resistant B-ALL xenografts dramatically sensitized tumors to PR-104 in vivo; AKR1C3 expression correlated with PR-104/PR-104A sensitivity across T-ALL and B-ALL xenografts and primary patient blasts.","method":"AKR1C3 overexpression by lentiviral transduction; patient-derived xenograft in vivo efficacy studies; in vitro cytotoxicity assays; AKR1C3 expression analysis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — causal demonstration by AKR1C3 overexpression-driven sensitization in vivo, correlation across multiple patient-derived models","pmids":["26116659"],"is_preprint":false},{"year":2015,"finding":"11β-PGF2α, a metabolite catalyzed by AKR1C3 from PGD2, stimulates the FP (prostaglandin F) receptor, phosphorylates ERK and CREB, and induces Slug expression in breast cancer cells expressing FP receptor, decreasing chemosensitivity.","method":"AKR1C3 metabolite identification; FP receptor-overexpressing MCF-7 cells; 11β-PGF2α treatment; Western blot (ERK/CREB phosphorylation); gene expression (Slug); chemosensitivity assays; IHC correlation in clinical specimens","journal":"Molecular and cellular endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined product-receptor-signaling pathway in cell model, IHC correlation, single lab","pmids":["26170067"],"is_preprint":false}],"current_model":"AKR1C3 is a multifunctional aldo-keto reductase that acts as a 17-ketosteroid reductase (converting androstenedione and 5α-androstanedione to testosterone and DHT), an 11-ketoprostaglandin reductase (converting PGD2 to 9α,11β-PGF2α and PGH2 to PGF2α via direct NADPH hydride transfer), and a 20-ketosteroid reductase (inactivating progesterone); beyond its catalytic roles, it functions as a non-enzymatic AR-selective coactivator by directly interacting with full-length AR and AR-V7 to stabilize these receptors from ubiquitin-mediated degradation and co-occupy androgen-responsive promoters, while also stabilizing the ubiquitin ligase Siah2; its expression is transcriptionally activated by the NRF2/MAFG heterodimer, ERG (TMPRSS2-ERG fusions), and the AHR, and is induced by insulin via the PI3K/AKT/mTOR/NRF2 axis in adipocytes; in cancer contexts, AKR1C3 drives castration-resistant prostate cancer by elevating intratumoral androgens and AR-V7 levels, promotes HCC proliferation and metastasis through an AKR1C3/NF-κB/STAT3 positive feedback loop and by suppressing ferroptosis via YAP/SLC7A11 signaling, mediates lipid droplet accumulation protecting cells from sorafenib-induced mitochondrial lipotoxicity, and confers chemoresistance to anthracyclines and other agents by metabolizing cytotoxic substrates."},"narrative":{"mechanistic_narrative":"AKR1C3 is a multifunctional, NADPH-dependent aldo-keto reductase that shapes intracellular hormone and prostaglandin milieus and, through both catalytic and non-enzymatic activities, drives proliferative and drug-resistant programs in hormone-dependent cancers [PMID:11165022, PMID:23995860]. Enzymatically it operates as a 3-, 17-, and 20-ketosteroid reductase, converting androstenedione and 5α-androstanedione to testosterone and DHT (with kinetic preference for 5α-reduced substrates) and additionally reducing 11-oxygenated androgens with even greater efficiency, while inactivating progesterone [PMID:11165022, PMID:35560164]. It also functions as a prostaglandin F synthase, converting PGD2 to 9α,11β-PGF2α and PGH2 to PGF2α by direct hydride transfer from bound NADPH to the endoperoxide without catalytic residue participation, generating products that signal through the FP receptor and PI3K/Akt or ERK/CREB pathways [PMID:16475787, PMID:18508192, PMID:26170067]. Beyond catalysis, AKR1C3 acts as a non-enzymatic, AR-selective coactivator: it physically binds full-length AR and the AR-V7 splice variant, co-occupies androgen-responsive promoters, and stabilizes these receptors against ubiquitin-mediated degradation; catalytically inactive AKR1C3 retains this function and likewise stabilizes the ubiquitin ligase Siah2 and PARP1 [PMID:23995860, PMID:26160177, PMID:31308078, PMID:35773412, PMID:36799021]. In prostate cancer it sustains intratumoral androgen synthesis and AR/AR-V7 activity, conferring resistance to enzalutamide, abiraterone, apalutamide, and darolutamide [PMID:25649766, PMID:27794047, PMID:32430485]. AKR1C3 expression is transcriptionally activated by ERG (TMPRSS2-ERG fusions), AR itself, the NRF2/MAFG heterodimer, and the AHR, and is induced by insulin via a PI3K/AKT/mTOR/NRF2 axis in adipocytes [PMID:25754347, PMID:31253396, PMID:35773412, PMID:36596844, PMID:36799021]. In hepatocellular carcinoma it drives proliferation and metastasis through an NF-κB/STAT3 positive feedback loop, suppresses ferroptosis via YAP/SLC7A11 signaling, and sustains lipid-droplet accumulation that protects from sorafenib-induced mitochondrial lipotoxicity [PMID:33361392, PMID:36920042, PMID:36451864]. AKR1C3 also activates the nitrogen-mustard prodrug PR-104A, making its expression a determinant of prodrug sensitivity [PMID:26116659].","teleology":[{"year":2001,"claim":"Establishing AKR1C3's intrinsic catalytic repertoire was the foundational question; reconstitution defined it as a broad-specificity hydroxysteroid oxidoreductase capable of generating active androgens.","evidence":"In vitro assays with homogeneous recombinant enzyme and kinetic analysis across multiple steroid substrates","pmids":["11165022"],"confidence":"High","gaps":["Did not address physiological tissue context or in-cell flux","Did not distinguish dominant in vivo reaction direction"]},{"year":2006,"claim":"How AKR1C3 catalyzes prostaglandin reduction was resolved structurally, showing direct NADPH hydride transfer to PGH2 without catalytic residues and mapping the PGD2/inhibitor binding site.","evidence":"X-ray crystallography at 2.0 Å with NADPH and bimatoprost plus inhibition assays","pmids":["16475787"],"confidence":"High","gaps":["Did not connect PGF synthase activity to a cellular phenotype"]},{"year":2008,"claim":"The functional consequence of PGD2 reduction was defined: AKR1C3-generated 9α,11β-PGF2α drives proliferation through FP receptor and PI3K/Akt signaling.","evidence":"Stable AKR1C3 overexpression in PC-3 cells with FP antagonist and PI3K inhibitor dissection","pmids":["18508192"],"confidence":"Medium","gaps":["Single overexpression model","Did not establish endogenous requirement"]},{"year":2009,"claim":"Whether AKR1C3 contributes to physiological androgen output was tested, establishing it as a mediator of adrenal testosterone production.","evidence":"siRNA knockdown in H295R adrenal cells plus in vivo adrenal vein sampling with ACTH","pmids":["19336506"],"confidence":"High","gaps":["Did not quantify AKR1C3's relative contribution versus other steroidogenic enzymes"]},{"year":2012,"claim":"Structural definition of the androstenedione-binding site and selectivity subpocket enabled rational design of AKR1C3-selective inhibitors over AKR1C1/AKR1C2.","evidence":"Crystallography of AKR1C3·NADP+·inhibitor complexes with enzymatic and AR reporter assays","pmids":["22507964","23432095"],"confidence":"High","gaps":["Inhibitor in vivo efficacy not established at this stage"]},{"year":2012,"claim":"Upstream regulation by growth/differentiation signaling was probed, identifying an activin A–AKR1C3–androgen feedback loop in prostate cancer.","evidence":"Activin A treatment and antagonism in prostate cancer cell lines and xenografts with testosterone measurement","pmids":["23024260"],"confidence":"Medium","gaps":["Direct transcriptional mechanism not defined","Single-lab finding"]},{"year":2013,"claim":"The pivotal discovery that AKR1C3 functions beyond catalysis: it physically interacts with AR and acts as an AR-selective coactivator promoting growth independently of steroidogenesis.","evidence":"Co-IP, ChIP, confocal co-localization, xenograft growth, and selective inhibitor treatment","pmids":["23995860"],"confidence":"High","gaps":["Structural basis of AR binding unresolved","Coactivator domain not mapped"]},{"year":2015,"claim":"The non-enzymatic role was mechanistically extended: AKR1C3 stabilizes the ubiquitin ligase Siah2 to enhance AR activity, with catalytically dead enzyme retaining function.","evidence":"Co-IP, Siah2 knockdown/re-expression of WT and catalytic-dead AKR1C3, ubiquitination and tumor assays","pmids":["26160177"],"confidence":"High","gaps":["Did not define the AKR1C3 surface mediating Siah2 binding"]},{"year":2015,"claim":"AKR1C3 was established as a clinically relevant driver of antiandrogen resistance via intracrine androgen synthesis and as a transcriptional target of TMPRSS2-ERG fusions.","evidence":"shRNA/overexpression, LC/MS androgen quantitation, ERG ChIP-seq, and in vivo drug sensitivity assays","pmids":["25649766","25754347"],"confidence":"High","gaps":["Relative weight of catalytic versus coactivator contribution to resistance not partitioned"]},{"year":2015,"claim":"AKR1C3's role beyond prostate was broadened: it activates the prodrug PR-104A, determining chemotherapeutic sensitivity, and its PGD2-derived metabolite drives breast cancer signaling and chemoresistance.","evidence":"AKR1C3 overexpression-driven PR-104 sensitization in leukemia PDX; 11β-PGF2α/FP/ERK-CREB-Slug pathway in FP-expressing MCF-7","pmids":["26116659","26170067"],"confidence":"High","gaps":["PR-104A activation chemistry not structurally detailed here"]},{"year":2015,"claim":"Endocrine regulation in adipose tissue was defined: insulin upregulates AKR1C3 to increase testosterone generation, linking hyperinsulinemia to hyperandrogenism.","evidence":"Insulin treatment of adipocytes with LC-MS/MS androgen measurement and in vivo DHEA challenge in insulin-receptor-mutation subjects","pmids":["26312838"],"confidence":"High","gaps":["Transcription factor mediating insulin induction not yet identified at this step"]},{"year":2016,"claim":"AKR1C3 was shown to mediate abiraterone resistance, generalizing its role across AR-pathway inhibitors and validating indomethacin as a resensitizing agent.","evidence":"Bidirectional overexpression/knockdown, androgen and AR activity measurement, in vivo indomethacin treatment","pmids":["27794047"],"confidence":"High","gaps":["Did not address AR-V7 contribution at this stage"]},{"year":2019,"claim":"The resistance mechanism was extended to AR-V7: AKR1C3 stabilizes the AR-V7 splice variant via the ubiquitin-proteasome pathway, with inhibition lowering AR/AR-V7 protein.","evidence":"Co-IP of AKR1C3-AR-V7, proteasome pathway analysis, indomethacin treatment, in vivo xenografts","pmids":["31308078"],"confidence":"High","gaps":["Mechanism of stabilization (E3 ligase competition or chaperoning) not resolved"]},{"year":2020,"claim":"The AKR1C3/AR-V7 axis was shown to drive cross-resistance to multiple antiandrogens and to repress the tumor suppressor B4GALT1 via reciprocal protein stabilization.","evidence":"shRNA epistasis across enzalutamide/apalutamide/darolutamide; Co-IP and B4GALT1 analysis in CRPC models","pmids":["32430485","32902124"],"confidence":"Medium","gaps":["Single-lab findings","Reciprocal stabilization mechanism not biochemically dissected"]},{"year":2020,"claim":"AKR1C3 was implicated in hepatocellular carcinoma through a self-reinforcing inflammatory circuit: it activates NF-κB via TRAF6, and STAT3 transcriptionally feeds back onto the AKR1C3 promoter.","evidence":"Gain/loss-of-function, NF-κB reporters, TRAF6 ubiquitination, STAT3 ChIP, in vivo assays","pmids":["33361392"],"confidence":"High","gaps":["Whether catalytic activity is required for TRAF6 modulation not isolated"]},{"year":2021,"claim":"Additional upstream activators were identified — AHR and PAH/EGFR signaling — linking environmental and xenobiotic exposure to AKR1C3 induction and doxorubicin resistance.","evidence":"AhR CRISPR knockout and promoter reporter in TNBC; EGFR inhibition, mutational and docking analysis with benzo[a]pyrene","pmids":["31253396","34991250"],"confidence":"Medium","gaps":["Single-lab findings","Integration with other AKR1C3 promoter inputs not modeled"]},{"year":2022,"claim":"Transcriptional control by NRF2/MAFG was established alongside a new non-enzymatic effector role, AKR1C3-mediated PARP1 stabilization driving HCC growth.","evidence":"NRF2/MAFG ChIP on AKR1C3 promoter, WT vs catalytic-mutant overexpression, PARP1 ubiquitination, in vivo assays","pmids":["35773412"],"confidence":"High","gaps":["Direct AKR1C3-PARP1 binding interface not defined"]},{"year":2022,"claim":"AKR1C3's metabolic role in HCC was defined: it sustains lipid-droplet formation that buffers cells against sorafenib-induced mitochondrial lipotoxicity.","evidence":"CRISPR knockout, isotopic tracing, multi-omics, Seahorse flux analysis, and inhibitor treatment","pmids":["36451864"],"confidence":"High","gaps":["Enzymatic substrate driving lipid-droplet phenotype not pinpointed"]},{"year":2022,"claim":"The biochemical scope of AKR1C3 androgen synthesis was refined to include kinetically superior reduction of 11-oxygenated androgens, relevant to PCOS hyperandrogenism.","evidence":"HPLC kinetic assays with recombinant AKR1C3 and isotope-dilution LC-HRMS in insulin-treated adipocytes","pmids":["35560164"],"confidence":"High","gaps":["In vivo dominance of 11-oxygenated versus classical pathway not quantified"]},{"year":2023,"claim":"Integration of the coactivator and metabolic roles was achieved: AKR1C3 non-enzymatically stabilizes AR to induce FASN and lipid droplets via PI3K/AKT/mTOR/NRF2, with bifunctional inhibitors required to block this output.","evidence":"Co-IP, proximity ligation, ChIP-qPCR co-occupancy at FASN, pathway inhibition, and monofunctional vs bifunctional inhibitor comparison","pmids":["36799021"],"confidence":"High","gaps":["Coactivator-deficient separation-of-function mutants not used"]},{"year":2023,"claim":"AR was shown to reciprocally regulate AKR1C3 through a distal enhancer, closing a feed-forward loop, and dual inhibitors (PTUPB) synergized with enzalutamide to suppress CRPC.","evidence":"AR ChIP on AKR1C3 enhancer, enzymatic assays, and VCaP/PDX organoid combination drug studies","pmids":["36596844"],"confidence":"Medium","gaps":["Single-lab finding","Enhancer interaction with NRF2/ERG inputs not integrated"]},{"year":null,"claim":"How AKR1C3 mechanistically distinguishes and balances its enzymatic versus AR/Siah2/PARP1-stabilizing coactivator functions — and the structural basis of its protein-protein interactions — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of AKR1C3 bound to AR, Siah2, or PARP1","Separation-of-function mutants distinguishing coactivator from catalytic roles not defined","In vivo dominance of competing downstream programs unquantified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,2,20]},{"term_id":"GO:0016209","term_label":"antioxidant activity","supporting_discovery_ids":[21]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[5,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[9,12,19]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,22]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,20,18]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,13,25,27]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,8,19,22,23]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,11,26]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[18,21]}],"complexes":[],"partners":["AR","AR-V7","SIAH2","PARP1","TRAF6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P42330","full_name":"Aldo-keto reductase family 1 member C3","aliases":["17-beta-hydroxysteroid dehydrogenase type 5","17-beta-HSD 5","3-alpha-HSD type II, brain","3-alpha-hydroxysteroid dehydrogenase type 2","3-alpha-HSD type 2","Chlordecone reductase homolog HAKRb","Dihydrodiol dehydrogenase 3","DD-3","DD3","Dihydrodiol dehydrogenase type I","HA1753","Prostaglandin F synthase","PGFS","Testosterone 17-beta-dehydrogenase 5"],"length_aa":323,"mass_kda":36.9,"function":"Cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids. Displays broad substrate specificity with distinct positional and stereochemistry, primarily generating 17beta-hydroxysteroids, but also 3alpha- and 20alpha-hydroxysteroids (PubMed:10998348, PubMed:11165022, PubMed:20036328, PubMed:9415401, PubMed:9927279, PubMed:10998348, PubMed:9927279). Produces potent androgens via classical and 'backdoor'/alternative pathways. In the classical androgen metabolic pathway (biosynthesis of 5alpha-dihydrotestosterone (5alpha-DHT) via testosterone), catalyzes the reduction of delta4-androstenedione to form testosterone (PubMed:10998348, PubMed:11165022, PubMed:20036328, PubMed:9415401, PubMed:9927279). In the 'backdoor' androgen metabolic pathway (biosynthesis of 5alpha-dihydrotestosterone (5alpha-DHT) via pregnanes), reduces androsterone to 5alpha-androstane-3alpha,17beta-diol preceding 5alpha-DHT secretion (PubMed:10557352, PubMed:10998348, PubMed:9415401). Reduces 5alpha-DHT to less potent androgen 5alpha-androstane-3alpha,17beta-diol, likely regulating ligand availability for androgen receptors (PubMed:10557352, PubMed:10998348, PubMed:11165022, PubMed:14672942, PubMed:7650035, PubMed:9415401). May contribute to the metabolism of adrenal-derived androgen precursors. Reduces 11-keto-4-androstene-3,17-dione (11KA4) and 11-keto-5alpha-androstane-3,17-dione (11K-Adione) into potent androgens 11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT), respectively (PubMed:31926269). In estrogen metabolism, catalyzes the conversion of estrone to potent estrogen 17beta-estradiol (PubMed:10998348, PubMed:11165022, PubMed:20036328). Acts as a prostaglandin (PG) F2alpha synthase. Displays 11-ketoreductase and 9,11-endoperoxide reductase activities and reduces PGD2 to 11beta-PGF2alpha and PGH2 to PGF2alpha (PubMed:10622721, PubMed:11165022, PubMed:15047184, PubMed:19010934, PubMed:20036328, PubMed:7650035, PubMed:9415401, PubMed:9927279). Also displays retinaldehyde reductase activity toward 9-cis-retinal (PubMed:21851338). In vitro can efficiently catalyze bidirectional conversion between ketosteroids and hydroxysteroids using NADPH/NADP(+) or NADH/NAD(+) as cofactors. In vivo however, the reductase activity prevails since the major reducing cofactor NADPH inhibits NAD(+)-dependent oxidase activity (PubMed:11165022, PubMed:14672942). In addition, it is able to reduce in vitro various carbonyl compounds like menadione, phenanthrenequinone and nitrobenzaldehyde (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/P42330/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/AKR1C3","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/AKR1C3","total_profiled":1310},"omim":[{"mim_id":"603966","title":"ALDO-KETO REDUCTASE FAMILY 1, MEMBER C3; AKR1C3","url":"https://www.omim.org/entry/603966"},{"mim_id":"600451","title":"ALDO-KETO REDUCTASE FAMILY 1, MEMBER C4; AKR1C4","url":"https://www.omim.org/entry/600451"},{"mim_id":"600450","title":"ALDO-KETO REDUCTASE FAMILY 1, MEMBER C2; AKR1C2","url":"https://www.omim.org/entry/600450"},{"mim_id":"600449","title":"ALDO-KETO REDUCTASE FAMILY 1, MEMBER C1; AKR1C1","url":"https://www.omim.org/entry/600449"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoli fibrillar center","reliability":"Additional"},{"location":"Endoplasmic reticulum","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"intestine","ntpm":415.2}],"url":"https://www.proteinatlas.org/search/AKR1C3"},"hgnc":{"alias_symbol":["KIAA0119","DDX","HAKRB","PGFS"],"prev_symbol":["HSD17B5"]},"alphafold":{"accession":"P42330","domains":[{"cath_id":"3.20.20.100","chopping":"8-312","consensus_level":"high","plddt":97.337,"start":8,"end":312}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P42330","model_url":"https://alphafold.ebi.ac.uk/files/AF-P42330-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P42330-F1-predicted_aligned_error_v6.png","plddt_mean":96.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=AKR1C3","jax_strain_url":"https://www.jax.org/strain/search?query=AKR1C3"},"sequence":{"accession":"P42330","fasta_url":"https://rest.uniprot.org/uniprotkb/P42330.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P42330/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P42330"}},"corpus_meta":[{"pmid":"25649766","id":"PMC_25649766","title":"Intracrine 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cancer","url":"https://pubmed.ncbi.nlm.nih.gov/15212687","citation_count":115,"is_preprint":false},{"pmid":"16601286","id":"PMC_16601286","title":"Increased expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen receptor in prostate carcinoma.","date":"2006","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16601286","citation_count":115,"is_preprint":false},{"pmid":"23995860","id":"PMC_23995860","title":"Steroidogenic enzyme AKR1C3 is a novel androgen receptor-selective coactivator that promotes prostate cancer growth.","date":"2013","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/23995860","citation_count":109,"is_preprint":false},{"pmid":"27794047","id":"PMC_27794047","title":"Inhibition of AKR1C3 Activation Overcomes Resistance to Abiraterone in Advanced Prostate Cancer.","date":"2016","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/27794047","citation_count":108,"is_preprint":false},{"pmid":"19336506","id":"PMC_19336506","title":"Type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3) contributes to testosterone production in the adrenal reticularis.","date":"2009","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/19336506","citation_count":102,"is_preprint":false},{"pmid":"33361392","id":"PMC_33361392","title":"A Positive Feedback Loop of AKR1C3-Mediated Activation of NF-κB and STAT3 Facilitates Proliferation and Metastasis in Hepatocellular Carcinoma.","date":"2020","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33361392","citation_count":96,"is_preprint":false},{"pmid":"30012349","id":"PMC_30012349","title":"AKR1C3 (type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase): Roles in malignancy and endocrine disorders.","date":"2018","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/30012349","citation_count":94,"is_preprint":false},{"pmid":"18632753","id":"PMC_18632753","title":"Bladder cancer risk and genetic variation in AKR1C3 and other metabolizing genes.","date":"2008","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/18632753","citation_count":90,"is_preprint":false},{"pmid":"11165022","id":"PMC_11165022","title":"Structure-function aspects and inhibitor design of type 5 17beta-hydroxysteroid dehydrogenase (AKR1C3).","date":"2001","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11165022","citation_count":88,"is_preprint":false},{"pmid":"23432095","id":"PMC_23432095","title":"Development of potent and selective indomethacin analogues for the inhibition of AKR1C3 (Type 5 17β-hydroxysteroid dehydrogenase/prostaglandin F synthase) in castrate-resistant prostate cancer.","date":"2013","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23432095","citation_count":86,"is_preprint":false},{"pmid":"31256877","id":"PMC_31256877","title":"Paralog Studies Augment Gene Discovery: DDX and DHX Genes.","date":"2019","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31256877","citation_count":77,"is_preprint":false},{"pmid":"32463235","id":"PMC_32463235","title":"Overview of AKR1C3: Inhibitor Achievements and Disease Insights.","date":"2020","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32463235","citation_count":76,"is_preprint":false},{"pmid":"32430485","id":"PMC_32430485","title":"Cross-Resistance Among Next-Generation Antiandrogen Drugs Through the AKR1C3/AR-V7 Axis in Advanced Prostate Cancer.","date":"2020","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/32430485","citation_count":69,"is_preprint":false},{"pmid":"25754347","id":"PMC_25754347","title":"ERG/AKR1C3/AR Constitutes a Feed-Forward Loop for AR Signaling in Prostate Cancer Cells.","date":"2015","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/25754347","citation_count":64,"is_preprint":false},{"pmid":"31308078","id":"PMC_31308078","title":"AKR1C3 Promotes AR-V7 Protein Stabilization and Confers Resistance to AR-Targeted Therapies in Advanced Prostate Cancer.","date":"2019","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/31308078","citation_count":63,"is_preprint":false},{"pmid":"19007764","id":"PMC_19007764","title":"AKR1C3 as a potential target for the inhibitory effect of dietary flavonoids.","date":"2008","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/19007764","citation_count":61,"is_preprint":false},{"pmid":"21134280","id":"PMC_21134280","title":"Elevated AKR1C3 expression promotes prostate cancer cell survival and prostate cell-mediated endothelial cell tube formation: implications for prostate cancer progression.","date":"2010","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21134280","citation_count":56,"is_preprint":false},{"pmid":"25514466","id":"PMC_25514466","title":"The DHEA-sulfate depot following P450c17 inhibition supports the case for AKR1C3 inhibition in high risk localized and advanced castration resistant prostate cancer.","date":"2014","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/25514466","citation_count":56,"is_preprint":false},{"pmid":"22507964","id":"PMC_22507964","title":"Crystal structures of AKR1C3 containing an N-(aryl)amino-benzoate inhibitor and a bifunctional AKR1C3 inhibitor and androgen receptor antagonist. Therapeutic leads for castrate resistant prostate cancer.","date":"2012","source":"Bioorganic & medicinal chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/22507964","citation_count":55,"is_preprint":false},{"pmid":"27385003","id":"PMC_27385003","title":"Overexpression of AKR1C3 significantly enhances human prostate cancer cells resistance to radiation.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27385003","citation_count":53,"is_preprint":false},{"pmid":"23608157","id":"PMC_23608157","title":"Distinct DDX DEAD-box RNA helicases cooperate to modulate the HIV-1 Rev function.","date":"2013","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23608157","citation_count":52,"is_preprint":false},{"pmid":"25661377","id":"PMC_25661377","title":"Aldo-keto reductase 1C3 (AKR1C3) is associated with the doxorubicin resistance in human breast cancer via PTEN loss.","date":"2014","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/25661377","citation_count":52,"is_preprint":false},{"pmid":"26116659","id":"PMC_26116659","title":"AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia.","date":"2015","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/26116659","citation_count":51,"is_preprint":false},{"pmid":"36451864","id":"PMC_36451864","title":"AKR1C3-dependent lipid droplet formation confers hepatocellular carcinoma cell adaptability to targeted therapy.","date":"2022","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/36451864","citation_count":50,"is_preprint":false},{"pmid":"23677986","id":"PMC_23677986","title":"Biosynthesis and degradation of canine placental prostaglandins: prepartum changes in expression and function of prostaglandin F2α-synthase (PGFS, AKR1C3) and 15-hydroxyprostaglandin dehydrogenase (HPGD).","date":"2013","source":"Biology of 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(2002)","url":"https://pubmed.ncbi.nlm.nih.gov/21039282","citation_count":14,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":59176,"output_tokens":8114,"usd":0.149619,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17753,"output_tokens":6203,"usd":0.12192,"stage2_stop_reason":"end_turn"},"total_usd":0.271539,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"Recombinant AKR1C3 expressed in E. coli functions as a 3-keto-, 17-keto- and 20-ketosteroid reductase and as a 3α-, 17β- and 20α-hydroxysteroid oxidase in vitro, reducing 5α-DHT, androstenedione, estrone and progesterone to produce 3α-androstanediol, testosterone, 17β-estradiol and 20α-hydroxyprogesterone respectively; kinetic analysis (kcat/Km) showed preference for 5α-dihydrotestosterone and 5α-androstane-3,17-dione as substrates.\",\n      \"method\": \"In vitro enzymatic assay with homogeneous recombinant protein expressed in E. coli; kinetic analysis (kcat/Km); RT-PCR for tissue distribution\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution with recombinant enzyme, multiple substrate assays with kinetic parameters, replicated across multiple steroid substrates\",\n      \"pmids\": [\"11165022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Crystal structure of prostaglandin F synthase (AKR1C3/PGFS) containing NADPH and bimatoprost at 2.0 Å resolution revealed the PGD2 binding site and proposed catalytic mechanism: PGF2α formation from PGH2 involves direct hydride transfer from bound NADPH to the 9,11-endoperoxide of PGH2 without participation of specific amino acid residues; bimatoprost binds near the PGD2 site with reversed chain orientation.\",\n      \"method\": \"X-ray crystallography (2.0 Å resolution), inhibition assays, model building\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure at 2.0 Å with functional inhibition data and mechanistic model building\",\n      \"pmids\": [\"16475787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"AKR1C3 converts PGD2 to 9α,11β-PGF2α via 11-ketoprostaglandin reductase activity; overexpression of AKR1C3 in PC-3 prostate cancer cells elevated cell proliferation in response to PGD2 stimulation; this proliferative signaling was mediated through the FP (prostaglandin F) receptor and downstream PI3K/Akt pathway.\",\n      \"method\": \"Stable transfection of PC-3 cells with AKR1C3 cDNA; cell proliferation assays; FP receptor antagonist (AL8810); PI3K inhibitor (LY294002); Western blot for Akt phosphorylation\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — stable overexpression with pharmacological pathway dissection, single lab, two orthogonal approaches (receptor antagonist + kinase inhibitor)\",\n      \"pmids\": [\"18508192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"AKR1C3 is expressed in human adrenal zona reticularis and mediates adrenal testosterone production: siRNA knockdown of AKR1C3 in H295R adrenal cells significantly inhibited testosterone production, and ACTH stimulation increased adrenal vein testosterone levels in vivo.\",\n      \"method\": \"siRNA knockdown in H295R cells; testosterone measurement; adrenal vein sampling with ACTH stimulation; microarray, RT-PCR, immunohistochemistry\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — siRNA loss-of-function with defined biochemical readout (testosterone production), orthogonal in vivo validation (adrenal vein sampling), replicated across multiple methods\",\n      \"pmids\": [\"19336506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Crystal structures of AKR1C3 in complex with NADP+ and two inhibitor compounds (an N-(aryl)amino-benzoate and a bifunctional inhibitor/AR antagonist) revealed that inhibitors bind in the androstenedione-binding site; one compound forms a unique 'double-decker' structure; a phenylamino ring projecting into a subpocket confers selectivity over AKR1C1/AKR1C2.\",\n      \"method\": \"X-ray crystallography of AKR1C3·NADP+·inhibitor complexes; enzymatic inhibition assays; AR reporter gene assays; Western blot\",\n      \"journal\": \"Bioorganic & medicinal chemistry letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures with functional inhibition data and cell-based validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22507964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AKR1C3 acts as a novel androgen receptor (AR)-selective enzymatic coactivator: it physically interacts with AR (demonstrated by co-immunoprecipitation), co-localizes with AR in prostate cancer cells and xenografts, is recruited to the promoter of an androgen-responsive gene (ChIP), and its coactivator function promotes prostate cancer cell and xenograft growth independently of its steroidogenic activity.\",\n      \"method\": \"Co-immunoprecipitation; chromatin immunoprecipitation (ChIP); confocal microscopy; stable transfection; xenograft growth assays; AR transactivation reporter assays; selective AKR1C3 inhibitor treatment\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, ChIP, co-localization, and functional xenograft studies; multiple orthogonal methods\",\n      \"pmids\": [\"23995860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of AKR1C3·NADP+·2'-des-methyl-indomethacin complex revealed a unique inhibitor binding mode, enabling rational design of indomethacin analogues with nanomolar potency, >100-fold selectivity over AKR1C1/AKR1C2, and blocking of testosterone formation in LNCaP-AKR1C3 cells.\",\n      \"method\": \"X-ray crystallography; enzymatic inhibition assays; cell-based testosterone formation assay\",\n      \"journal\": \"Journal of medicinal chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with functional enzyme inhibition assays and cell-based validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23432095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AKR1C3 mediates resistance to enzalutamide in prostate cancer through intracrine androgen synthesis: shRNA knockdown or indomethacin inhibition of AKR1C3 resensitized enzalutamide-resistant cells to enzalutamide both in vitro and in vivo; overexpression of AKR1C3 was sufficient to confer resistance; LC/MS analysis confirmed elevated androgen precursors and androgens in resistant cells.\",\n      \"method\": \"shRNA knockdown; AKR1C3 overexpression; global gene expression analysis; LC/MS metabolite analysis; in vitro and in vivo (xenograft) drug sensitivity assays; indomethacin inhibition\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic manipulation (KD and OE), orthogonal pharmacological validation, metabolite quantification, both in vitro and in vivo readouts\",\n      \"pmids\": [\"25649766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERG (from TMPRSS2-ERG fusion) directly binds the AKR1C3 gene and regulates its expression; ERG knockdown reduced AKR1C3 expression, decreased DHT synthesis from 5α-androstanedione, and reduced PSA expression in VCaP cells, establishing an ERG/AKR1C3/AR feed-forward loop in prostate cancer.\",\n      \"method\": \"Lentivirus-mediated ERG knockdown; ChIP-seq (ERG binding to AKR1C3 gene); LC-MS androgen quantitation; gene expression analysis; immunohistochemistry\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq for direct binding, loss-of-function with defined biochemical (DHT, PSA) readouts, multiple orthogonal methods\",\n      \"pmids\": [\"25754347\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AKR1C3 stabilizes the ubiquitin ligase Siah2 by physically binding to Siah2 and inhibiting its self-ubiquitination and degradation, thereby enhancing Siah2-dependent AR transcriptional activity in prostate cancer cells; both wild-type and catalytically inactive AKR1C3 partially rescued AR activity and growth defects in Siah2 knockdown cells, indicating a non-enzymatic role.\",\n      \"method\": \"Co-immunoprecipitation (AKR1C3-Siah2 interaction); Siah2 knockdown with re-expression of WT and catalytically inactive AKR1C3; ubiquitination assays; in vitro and orthotopic tumor growth assays; androgen level measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP demonstrating direct binding, ubiquitination assay, catalytically inactive mutant rescue distinguishing enzymatic from non-enzymatic roles, in vivo validation\",\n      \"pmids\": [\"26160177\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Insulin upregulates AKR1C3 expression and activity in subcutaneous adipocytes in vitro, driving increased testosterone generation from androstenedione; in vivo DHEA challenge in women with insulin receptor mutations showed elevated testosterone production correlating with AKR1C3 induction.\",\n      \"method\": \"In vitro insulin treatment of differentiated adipocytes; AKR1C3 expression by real-time PCR; androgen measurement by LC-MS/MS; in vivo DHEA challenge with serial blood androgen measurement\",\n      \"journal\": \"Lancet\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — orthogonal in vitro and in vivo experiments, quantitative hormone measurements, replicated across multiple subject groups\",\n      \"pmids\": [\"26312838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"AKR1C3 activation is a critical mechanism of resistance to abiraterone: overexpression of AKR1C3 conferred abiraterone resistance while downregulation resensitized resistant cells; AKR1C3 increases intracrine androgen synthesis and enhances AR transcriptional activity in abiraterone-resistant cells; indomethacin treatment overcame resistance both in vitro and in vivo.\",\n      \"method\": \"AKR1C3 overexpression and shRNA knockdown; intracrine androgen measurement; AR transcriptional activity assays; in vitro and in vivo (xenograft) drug sensitivity assays; indomethacin treatment\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic manipulation, androgen quantification, AR functional readout, both in vitro and in vivo validation\",\n      \"pmids\": [\"27794047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"AKR1C3 increases AR-V7 protein stability in enzalutamide-resistant prostate cancer cells through the ubiquitin-mediated proteasome pathway; the AKR1C3/AR-V7 complex collaboratively confers resistance to AR-targeted therapies; indomethacin targeting AKR1C3 decreases AR/AR-V7 protein expression both in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation (AKR1C3-AR-V7 interaction); proteasome pathway analysis; indomethacin treatment; Western blot; bioinformatic pathway analysis; in vivo xenograft studies\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct interaction, proteasome pathway analysis, pharmacological inhibition with in vivo validation\",\n      \"pmids\": [\"31308078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AKR1C3 promotes HCC cell proliferation and metastasis by activating NF-κB signaling through modulation of TRAF6 and inducing its autoubiquitination; activated NF-κB releases proinflammatory factors that phosphorylate STAT3; STAT3 directly binds the AKR1C3 promoter and increases AKR1C3 transcription, forming a positive feedback loop; AKR1C3/NF-κB/STAT3 axis was validated by gain- and loss-of-function experiments.\",\n      \"method\": \"Gain- and loss-of-function experiments (overexpression and knockdown); NF-κB reporter assays; TRAF6 ubiquitination assays; STAT3 ChIP on AKR1C3 promoter; in vitro and in vivo (xenograft) proliferation and invasion assays; AKR1C3 inhibitor treatment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional genetic manipulation, promoter ChIP, ubiquitination assay, orthogonal in vitro and in vivo validation\",\n      \"pmids\": [\"33361392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The AKR1C3/AR-V7 axis confers cross-resistance to enzalutamide, abiraterone, apalutamide, and darolutamide; knockdown of AR-V7 resensitized enzalutamide-resistant cells to apalutamide and darolutamide; targeting AKR1C3 resensitized resistant cells through AR-V7 inhibition.\",\n      \"method\": \"shRNA knockdown of AR-V7 and AKR1C3; drug sensitivity assays; gene expression analysis\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis with shRNA knockdowns defining pathway order (AKR1C3→AR-V7→resistance), single lab\",\n      \"pmids\": [\"32430485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"AKR1C3/AR-V7 complex maintains CRPC tumor growth by repressing B4GALT1 (a tumor suppressor gene) expression; AKR1C3 interacts with AR-V7 protein in CRPC cells and reciprocally inhibits AR-V7 and AKR1C3 protein degradation.\",\n      \"method\": \"Co-immunoprecipitation; immunohistochemistry in clinical specimens; in vitro and in vivo (xenograft) tumor growth assays; B4GALT1 expression analysis\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for direct interaction, in vivo validation, single lab\",\n      \"pmids\": [\"32902124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"AHR (aryl hydrocarbon receptor) transcriptionally activates AKR1C3 expression in triple-negative breast cancer cells: AhR knockout decreased AKR1C3 expression; AhR enhanced AKR1C3 promoter reporter activity; reduced AKR1C3 enhanced doxorubicin sensitivity, linking AhR→AKR1C3→doxorubicin resistance.\",\n      \"method\": \"AhR CRISPR/Cas9 knockout; AKR1C3 promoter reporter assay; AKR1C3 siRNA knockdown; cell viability assays with doxorubicin; Western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assay for direct transcriptional regulation, genetic KO and KD with defined functional readouts, single lab\",\n      \"pmids\": [\"31253396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PAH exposure (benzo[a]pyrene) induces AKR1C3 expression and 11-ketoreduction of prostaglandin D2 through an EGFR-dependent pathway: B[a]P causes c-Src-mediated EGFR phosphorylation and auto/paracrine EGFR activation; EGFR inhibition blocks B[a]P-induced AKR1C3 upregulation; DLCs (PCB126) block EGFR activation by binding its extracellular domain, explaining differential AHR ligand responses.\",\n      \"method\": \"EGFR inhibition; receptor binding and internalization assays; mutational amino acid exchange; docking analyses; nanopore long-read RNA-seq; kinase inhibitor studies\",\n      \"journal\": \"Environment international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutational analysis, receptor binding assays, pharmacological inhibition, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34991250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"AKR1C3-dependent lipid droplet (LD) formation is required for sorafenib resistance in HCC: CRISPR/Cas9 knockout of AKR1C3 fully depletes LD contents and redirects FA flux to phospholipids, sphingolipids, and mitochondria; AKR1C3-dependent LD accumulation protects cells from sorafenib-induced mitochondrial lipotoxicity; pharmacological inhibition of AKR1C3 induces autophagy-dependent LD catabolism, mitochondrial fission, and apoptosis.\",\n      \"method\": \"CRISPR/Cas9 gene editing; isotopic tracing with deuterium-labeled palmitate and 13C-labeled glucose; proteomics and metabolomics; Seahorse metabolic flux analysis; immunoblotting; immunofluorescence; AKR1C3 inhibitor treatment\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — CRISPR/Cas9 genetic manipulation, isotopic tracing, multi-omics, and functional metabolic assays with multiple orthogonal methods\",\n      \"pmids\": [\"36451864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NRF2/MAFG transcription factor heterodimer directly binds the AKR1C3 promoter to activate its transcription; AKR1C3 in turn stabilizes PARP1 by decreasing its ubiquitination, promoting HCC cell proliferation; both catalytic and non-catalytic AKR1C3 functions drive tumor growth.\",\n      \"method\": \"ChIP (NRF2/MAFG binding to AKR1C3 promoter); AKR1C3 WT and catalytic mutant overexpression; PARP1 ubiquitination assay; in vitro and in vivo xenograft assays; AKR1C3 shRNA intratumoral injection\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for direct promoter binding, ubiquitination assay, WT vs. catalytic mutant comparison revealing non-enzymatic role, in vivo validation\",\n      \"pmids\": [\"35773412\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Insulin-induced AKR1C3 in PCOS adipocytes converts both classical (androstenedione→testosterone) and 11-oxygenated androgens (11K-4AD→11K-T; 11K-5AD→11K-DHT) to potent androgens; conversion of 11-oxygenated androgens was kinetically superior to classical androgen formation by recombinant AKR1C3; 11K-T formed in adipocytes is subsequently inactivated by HSD11B1.\",\n      \"method\": \"HPLC discontinuous kinetic assays with recombinant AKR1C3; stable isotope dilution LC-HRMS quantitation of androgens in insulin-treated SGBS adipocytes; AKR1C3-deficient cell experiments\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with recombinant enzyme plus cell-based isotope tracing, multiple substrates characterized kinetically\",\n      \"pmids\": [\"35560164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AKR1C3 suppresses ferroptosis in HCC through YAP/SLC7A11 signaling: AKR1C3 knockdown decreased YAP nuclear translocation, inhibited cystine transporter SLC7A11, increased intracellular ferrous iron, and induced ferroptosis; overexpression of AKR1C3 protected against ferroptosis.\",\n      \"method\": \"AKR1C3 knockdown and overexpression; YAP nuclear localization assay; SLC7A11 expression analysis; ferrous iron measurement; ferroptosis inducer sensitivity assays in vitro and in vivo\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional genetic manipulation with defined pathway (YAP→SLC7A11) mechanistic dissection, single lab\",\n      \"pmids\": [\"36920042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AKR1C3 stabilizes AR in a non-enzymatic manner to induce FASN (fatty acid synthase) in PCOS adipocytes: insulin-induced AKR1C3 activates FASN through a PI3K/AKT/mTOR/NRF2 pathway in an AKR1C3- and AR-dependent manner; AKR1C3 interacts with AR (Co-IP, proximity ligation assay), co-occupies the FASN locus (ChIP-qPCR), and stabilizes AR from degradation; bifunctional but not monofunctional AKR1C3 inhibitors blocked FASN induction and lipid droplet formation.\",\n      \"method\": \"Co-immunoprecipitation; proximity ligation assay; ChIP-qPCR (AKR1C3 and AR co-occupancy at FASN promoter); pharmacological inhibition (PI3K/AKT/mTOR/NRF2 pathway); monofunctional vs. bifunctional inhibitor comparison; insulin treatment of SGBS adipocytes\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, PLA, ChIP-qPCR) demonstrating direct AKR1C3-AR interaction at target locus, pharmacological dissection of enzymatic vs. non-enzymatic roles\",\n      \"pmids\": [\"36799021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Full-length androgen receptor (AR-FL) reciprocally regulates AKR1C3 expression by binding to a distal enhancer region of the AKR1C3 gene; PTUPB, a novel dual inhibitor, suppresses AKR1C3 activity more effectively than indomethacin or celecoxib, and synergizes with enzalutamide to suppress CRPC tumor growth by blocking AR/AR-V7 signaling.\",\n      \"method\": \"AR ChIP on AKR1C3 distal enhancer; AKR1C3 enzymatic activity assays; VCaP xenograft and patient-derived xenograft organoid experiments; combination drug treatment\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct AR binding to AKR1C3 enhancer, functional in vivo validation, single lab\",\n      \"pmids\": [\"36596844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Activin A induces AKR1C3 expression and enzymatic activity (testosterone synthesis) in prostate cancer LNCaP and VCaP cells; inhibition of endogenous activin A in PC-3 cells decreased AKR1C3 levels and testosterone synthesis; androgens in turn suppress INHBA (activin A subunit) expression, forming a regulatory feedback.\",\n      \"method\": \"Activin A treatment and antagonist inhibition in prostate cancer cell lines and xenograft models; RT-PCR and protein expression; testosterone measurement; PC xenograft gene expression analysis\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional modulation of activin A with defined biochemical readouts, validated in multiple cell lines and xenograft models\",\n      \"pmids\": [\"23024260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AKR1C3 promotes prostate cancer metastasis by activating ERK signaling to drive epithelial-mesenchymal transition (EMT): knockdown of AKR1C3 or inhibition of its enzymatic activity suppressed cell migration/invasion, increased E-cadherin, decreased vimentin, and downregulated ERK phosphorylation and EMT transcription factors (ZEB1, TWIST1, SLUG) in vitro; AKR1C3 knockdown also reversed EMT and suppressed tumor growth in xenografts.\",\n      \"method\": \"shRNA knockdown of AKR1C3; chemical inhibitor treatment; wound healing and Transwell invasion assays; Western blot for EMT markers and phospho-ERK; subcutaneous xenograft experiments; IHC on clinical specimens\",\n      \"journal\": \"Urologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological inhibition with defined pathway (ERK→EMT) and in vivo validation, single lab\",\n      \"pmids\": [\"30139661\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AKR1C3 is the critical enzyme activating the nitrogen mustard prodrug PR-104A: overexpression of AKR1C3 in resistant B-ALL xenografts dramatically sensitized tumors to PR-104 in vivo; AKR1C3 expression correlated with PR-104/PR-104A sensitivity across T-ALL and B-ALL xenografts and primary patient blasts.\",\n      \"method\": \"AKR1C3 overexpression by lentiviral transduction; patient-derived xenograft in vivo efficacy studies; in vitro cytotoxicity assays; AKR1C3 expression analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — causal demonstration by AKR1C3 overexpression-driven sensitization in vivo, correlation across multiple patient-derived models\",\n      \"pmids\": [\"26116659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"11β-PGF2α, a metabolite catalyzed by AKR1C3 from PGD2, stimulates the FP (prostaglandin F) receptor, phosphorylates ERK and CREB, and induces Slug expression in breast cancer cells expressing FP receptor, decreasing chemosensitivity.\",\n      \"method\": \"AKR1C3 metabolite identification; FP receptor-overexpressing MCF-7 cells; 11β-PGF2α treatment; Western blot (ERK/CREB phosphorylation); gene expression (Slug); chemosensitivity assays; IHC correlation in clinical specimens\",\n      \"journal\": \"Molecular and cellular endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined product-receptor-signaling pathway in cell model, IHC correlation, single lab\",\n      \"pmids\": [\"26170067\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"AKR1C3 is a multifunctional aldo-keto reductase that acts as a 17-ketosteroid reductase (converting androstenedione and 5α-androstanedione to testosterone and DHT), an 11-ketoprostaglandin reductase (converting PGD2 to 9α,11β-PGF2α and PGH2 to PGF2α via direct NADPH hydride transfer), and a 20-ketosteroid reductase (inactivating progesterone); beyond its catalytic roles, it functions as a non-enzymatic AR-selective coactivator by directly interacting with full-length AR and AR-V7 to stabilize these receptors from ubiquitin-mediated degradation and co-occupy androgen-responsive promoters, while also stabilizing the ubiquitin ligase Siah2; its expression is transcriptionally activated by the NRF2/MAFG heterodimer, ERG (TMPRSS2-ERG fusions), and the AHR, and is induced by insulin via the PI3K/AKT/mTOR/NRF2 axis in adipocytes; in cancer contexts, AKR1C3 drives castration-resistant prostate cancer by elevating intratumoral androgens and AR-V7 levels, promotes HCC proliferation and metastasis through an AKR1C3/NF-κB/STAT3 positive feedback loop and by suppressing ferroptosis via YAP/SLC7A11 signaling, mediates lipid droplet accumulation protecting cells from sorafenib-induced mitochondrial lipotoxicity, and confers chemoresistance to anthracyclines and other agents by metabolizing cytotoxic substrates.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"AKR1C3 is a multifunctional, NADPH-dependent aldo-keto reductase that shapes intracellular hormone and prostaglandin milieus and, through both catalytic and non-enzymatic activities, drives proliferative and drug-resistant programs in hormone-dependent cancers [#0, #5]. Enzymatically it operates as a 3-, 17-, and 20-ketosteroid reductase, converting androstenedione and 5\\u03b1-androstanedione to testosterone and DHT (with kinetic preference for 5\\u03b1-reduced substrates) and additionally reducing 11-oxygenated androgens with even greater efficiency, while inactivating progesterone [#0, #20]. It also functions as a prostaglandin F synthase, converting PGD2 to 9\\u03b1,11\\u03b2-PGF2\\u03b1 and PGH2 to PGF2\\u03b1 by direct hydride transfer from bound NADPH to the endoperoxide without catalytic residue participation, generating products that signal through the FP receptor and PI3K/Akt or ERK/CREB pathways [#1, #2, #27]. Beyond catalysis, AKR1C3 acts as a non-enzymatic, AR-selective coactivator: it physically binds full-length AR and the AR-V7 splice variant, co-occupies androgen-responsive promoters, and stabilizes these receptors against ubiquitin-mediated degradation; catalytically inactive AKR1C3 retains this function and likewise stabilizes the ubiquitin ligase Siah2 and PARP1 [#5, #9, #12, #19, #22]. In prostate cancer it sustains intratumoral androgen synthesis and AR/AR-V7 activity, conferring resistance to enzalutamide, abiraterone, apalutamide, and darolutamide [#7, #11, #14]. AKR1C3 expression is transcriptionally activated by ERG (TMPRSS2-ERG fusions), AR itself, the NRF2/MAFG heterodimer, and the AHR, and is induced by insulin via a PI3K/AKT/mTOR/NRF2 axis in adipocytes [#8, #16, #19, #23, #22]. In hepatocellular carcinoma it drives proliferation and metastasis through an NF-\\u03baB/STAT3 positive feedback loop, suppresses ferroptosis via YAP/SLC7A11 signaling, and sustains lipid-droplet accumulation that protects from sorafenib-induced mitochondrial lipotoxicity [#13, #21, #18]. AKR1C3 also activates the nitrogen-mustard prodrug PR-104A, making its expression a determinant of prodrug sensitivity [#26].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing AKR1C3's intrinsic catalytic repertoire was the foundational question; reconstitution defined it as a broad-specificity hydroxysteroid oxidoreductase capable of generating active androgens.\",\n      \"evidence\": \"In vitro assays with homogeneous recombinant enzyme and kinetic analysis across multiple steroid substrates\",\n      \"pmids\": [\"11165022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address physiological tissue context or in-cell flux\", \"Did not distinguish dominant in vivo reaction direction\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"How AKR1C3 catalyzes prostaglandin reduction was resolved structurally, showing direct NADPH hydride transfer to PGH2 without catalytic residues and mapping the PGD2/inhibitor binding site.\",\n      \"evidence\": \"X-ray crystallography at 2.0 \\u00c5 with NADPH and bimatoprost plus inhibition assays\",\n      \"pmids\": [\"16475787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect PGF synthase activity to a cellular phenotype\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The functional consequence of PGD2 reduction was defined: AKR1C3-generated 9\\u03b1,11\\u03b2-PGF2\\u03b1 drives proliferation through FP receptor and PI3K/Akt signaling.\",\n      \"evidence\": \"Stable AKR1C3 overexpression in PC-3 cells with FP antagonist and PI3K inhibitor dissection\",\n      \"pmids\": [\"18508192\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single overexpression model\", \"Did not establish endogenous requirement\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Whether AKR1C3 contributes to physiological androgen output was tested, establishing it as a mediator of adrenal testosterone production.\",\n      \"evidence\": \"siRNA knockdown in H295R adrenal cells plus in vivo adrenal vein sampling with ACTH\",\n      \"pmids\": [\"19336506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not quantify AKR1C3's relative contribution versus other steroidogenic enzymes\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Structural definition of the androstenedione-binding site and selectivity subpocket enabled rational design of AKR1C3-selective inhibitors over AKR1C1/AKR1C2.\",\n      \"evidence\": \"Crystallography of AKR1C3\\u00b7NADP+\\u00b7inhibitor complexes with enzymatic and AR reporter assays\",\n      \"pmids\": [\"22507964\", \"23432095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Inhibitor in vivo efficacy not established at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Upstream regulation by growth/differentiation signaling was probed, identifying an activin A\\u2013AKR1C3\\u2013androgen feedback loop in prostate cancer.\",\n      \"evidence\": \"Activin A treatment and antagonism in prostate cancer cell lines and xenografts with testosterone measurement\",\n      \"pmids\": [\"23024260\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct transcriptional mechanism not defined\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The pivotal discovery that AKR1C3 functions beyond catalysis: it physically interacts with AR and acts as an AR-selective coactivator promoting growth independently of steroidogenesis.\",\n      \"evidence\": \"Co-IP, ChIP, confocal co-localization, xenograft growth, and selective inhibitor treatment\",\n      \"pmids\": [\"23995860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of AR binding unresolved\", \"Coactivator domain not mapped\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The non-enzymatic role was mechanistically extended: AKR1C3 stabilizes the ubiquitin ligase Siah2 to enhance AR activity, with catalytically dead enzyme retaining function.\",\n      \"evidence\": \"Co-IP, Siah2 knockdown/re-expression of WT and catalytic-dead AKR1C3, ubiquitination and tumor assays\",\n      \"pmids\": [\"26160177\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the AKR1C3 surface mediating Siah2 binding\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"AKR1C3 was established as a clinically relevant driver of antiandrogen resistance via intracrine androgen synthesis and as a transcriptional target of TMPRSS2-ERG fusions.\",\n      \"evidence\": \"shRNA/overexpression, LC/MS androgen quantitation, ERG ChIP-seq, and in vivo drug sensitivity assays\",\n      \"pmids\": [\"25649766\", \"25754347\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative weight of catalytic versus coactivator contribution to resistance not partitioned\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"AKR1C3's role beyond prostate was broadened: it activates the prodrug PR-104A, determining chemotherapeutic sensitivity, and its PGD2-derived metabolite drives breast cancer signaling and chemoresistance.\",\n      \"evidence\": \"AKR1C3 overexpression-driven PR-104 sensitization in leukemia PDX; 11\\u03b2-PGF2\\u03b1/FP/ERK-CREB-Slug pathway in FP-expressing MCF-7\",\n      \"pmids\": [\"26116659\", \"26170067\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"PR-104A activation chemistry not structurally detailed here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Endocrine regulation in adipose tissue was defined: insulin upregulates AKR1C3 to increase testosterone generation, linking hyperinsulinemia to hyperandrogenism.\",\n      \"evidence\": \"Insulin treatment of adipocytes with LC-MS/MS androgen measurement and in vivo DHEA challenge in insulin-receptor-mutation subjects\",\n      \"pmids\": [\"26312838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transcription factor mediating insulin induction not yet identified at this step\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"AKR1C3 was shown to mediate abiraterone resistance, generalizing its role across AR-pathway inhibitors and validating indomethacin as a resensitizing agent.\",\n      \"evidence\": \"Bidirectional overexpression/knockdown, androgen and AR activity measurement, in vivo indomethacin treatment\",\n      \"pmids\": [\"27794047\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address AR-V7 contribution at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The resistance mechanism was extended to AR-V7: AKR1C3 stabilizes the AR-V7 splice variant via the ubiquitin-proteasome pathway, with inhibition lowering AR/AR-V7 protein.\",\n      \"evidence\": \"Co-IP of AKR1C3-AR-V7, proteasome pathway analysis, indomethacin treatment, in vivo xenografts\",\n      \"pmids\": [\"31308078\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of stabilization (E3 ligase competition or chaperoning) not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The AKR1C3/AR-V7 axis was shown to drive cross-resistance to multiple antiandrogens and to repress the tumor suppressor B4GALT1 via reciprocal protein stabilization.\",\n      \"evidence\": \"shRNA epistasis across enzalutamide/apalutamide/darolutamide; Co-IP and B4GALT1 analysis in CRPC models\",\n      \"pmids\": [\"32430485\", \"32902124\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings\", \"Reciprocal stabilization mechanism not biochemically dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"AKR1C3 was implicated in hepatocellular carcinoma through a self-reinforcing inflammatory circuit: it activates NF-\\u03baB via TRAF6, and STAT3 transcriptionally feeds back onto the AKR1C3 promoter.\",\n      \"evidence\": \"Gain/loss-of-function, NF-\\u03baB reporters, TRAF6 ubiquitination, STAT3 ChIP, in vivo assays\",\n      \"pmids\": [\"33361392\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether catalytic activity is required for TRAF6 modulation not isolated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Additional upstream activators were identified \\u2014 AHR and PAH/EGFR signaling \\u2014 linking environmental and xenobiotic exposure to AKR1C3 induction and doxorubicin resistance.\",\n      \"evidence\": \"AhR CRISPR knockout and promoter reporter in TNBC; EGFR inhibition, mutational and docking analysis with benzo[a]pyrene\",\n      \"pmids\": [\"31253396\", \"34991250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings\", \"Integration with other AKR1C3 promoter inputs not modeled\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Transcriptional control by NRF2/MAFG was established alongside a new non-enzymatic effector role, AKR1C3-mediated PARP1 stabilization driving HCC growth.\",\n      \"evidence\": \"NRF2/MAFG ChIP on AKR1C3 promoter, WT vs catalytic-mutant overexpression, PARP1 ubiquitination, in vivo assays\",\n      \"pmids\": [\"35773412\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct AKR1C3-PARP1 binding interface not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"AKR1C3's metabolic role in HCC was defined: it sustains lipid-droplet formation that buffers cells against sorafenib-induced mitochondrial lipotoxicity.\",\n      \"evidence\": \"CRISPR knockout, isotopic tracing, multi-omics, Seahorse flux analysis, and inhibitor treatment\",\n      \"pmids\": [\"36451864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Enzymatic substrate driving lipid-droplet phenotype not pinpointed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The biochemical scope of AKR1C3 androgen synthesis was refined to include kinetically superior reduction of 11-oxygenated androgens, relevant to PCOS hyperandrogenism.\",\n      \"evidence\": \"HPLC kinetic assays with recombinant AKR1C3 and isotope-dilution LC-HRMS in insulin-treated adipocytes\",\n      \"pmids\": [\"35560164\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo dominance of 11-oxygenated versus classical pathway not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Integration of the coactivator and metabolic roles was achieved: AKR1C3 non-enzymatically stabilizes AR to induce FASN and lipid droplets via PI3K/AKT/mTOR/NRF2, with bifunctional inhibitors required to block this output.\",\n      \"evidence\": \"Co-IP, proximity ligation, ChIP-qPCR co-occupancy at FASN, pathway inhibition, and monofunctional vs bifunctional inhibitor comparison\",\n      \"pmids\": [\"36799021\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coactivator-deficient separation-of-function mutants not used\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"AR was shown to reciprocally regulate AKR1C3 through a distal enhancer, closing a feed-forward loop, and dual inhibitors (PTUPB) synergized with enzalutamide to suppress CRPC.\",\n      \"evidence\": \"AR ChIP on AKR1C3 enhancer, enzymatic assays, and VCaP/PDX organoid combination drug studies\",\n      \"pmids\": [\"36596844\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding\", \"Enhancer interaction with NRF2/ERG inputs not integrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How AKR1C3 mechanistically distinguishes and balances its enzymatic versus AR/Siah2/PARP1-stabilizing coactivator functions \\u2014 and the structural basis of its protein-protein interactions \\u2014 remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of AKR1C3 bound to AR, Siah2, or PARP1\", \"Separation-of-function mutants distinguishing coactivator from catalytic roles not defined\", \"In vivo dominance of competing downstream programs unquantified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 2, 20]},\n      {\"term_id\": \"GO:0016209\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [5, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [9, 12, 19]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 22]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 20, 18]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 13, 25, 27]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 8, 19, 22, 23]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 11, 26]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [18, 21]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AR\", \"AR-V7\", \"Siah2\", \"PARP1\", \"TRAF6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}