{"gene":"HSD3B1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1989,"finding":"HSD3B1 encodes the enzyme 3β-hydroxysteroid dehydrogenase that catalyzes the oxidative conversion of Δ5-3β-hydroxy steroids to the Δ4-3-keto configuration, which is required for the biosynthesis of all classes of steroid hormones including progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. The gene was chromosomally assigned to the p13 band of chromosome 1 by in situ hybridization.","method":"In situ hybridization with labeled HSD3B1-specific cDNA; enzymatic activity established by prior biochemical characterization","journal":"Cytogenetics and cell genetics","confidence":"High","confidence_rationale":"Tier 1 — foundational enzymatic characterization replicated across many labs; chromosomal assignment confirmed by in situ hybridization","pmids":["2630193"],"is_preprint":false},{"year":2004,"finding":"Placental-specific expression of HSD3B1 is determined by a 53-bp enhancer element located between -2570 and -2518 of the promoter, where TEF-5 (transcription enhancer factor-5) and a GATA-like protein coordinately bind two adjacent sites; site-specific mutations in either binding site completely abolished enhancer activity.","method":"Promoter deletion analysis, EMSA, site-directed mutagenesis, transfection of luciferase reporter constructs into JEG-3 cells","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods (EMSA, mutagenesis, reporter assays) in a single rigorous study","pmids":["15131259"],"is_preprint":false},{"year":2017,"finding":"GATA2 and GATA3 bind two GATA elements at -106/-99 and -52/-45 of the HSD3B1 proximal promoter. ChIP assays demonstrated GATA2 (but not GATA3) association with these regions in JEG-3 cells. GATA2 knockdown significantly reduced HSD3B1 expression, while GATA3 knockdown increased it, identifying GATA2 as a positive and GATA3 as a negative transcriptional regulator of HSD3B1 in human placenta.","method":"EMSA, ChIP assay, siRNA knockdown, luciferase reporter assay, Western blot","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods (EMSA, ChIP, knockdown, reporter assay) in single study","pmids":["28655875"],"is_preprint":false},{"year":2018,"finding":"Androgen receptor (AR) signaling transcriptionally induces HSD3B1 expression in prostate cancer cells (VCaP, CWR22Rv1, LNCaP, LAPC4) with peak induction at ~72 hours followed by attenuation at ~120 hours. Enzalutamide treatment abrogated androgen-induced HSD3B1 upregulation. In VCaP xenografts, castration reduced HSD3B1 expression in vivo. Androgen treatment increased metabolic flux from [3H]-DHEA to androstenedione, establishing a feed-forward loop of androgen synthesis.","method":"RT-PCR, Western blot, enzalutamide treatment (AR inhibition), in vivo xenograft castration model, radiolabeled substrate metabolic flux assay","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (transcriptional induction, protein levels, in vivo model, metabolic flux) in single study","pmids":["29850791"],"is_preprint":false},{"year":2018,"finding":"The HSD3B1(1245A>C) variant encodes a hyperactive 3βHSD1 protein (Thr367 variant) that increases metabolic flux from extragonadal precursor steroids (DHEA) to DHT synthesis in prostate cancer. Patients inheriting the 1245C variant have a stepwise increase in serum 3-keto-5α-abiraterone (an AR-stimulating abiraterone metabolite generated by 3βHSD1 action on abiraterone), demonstrating that 3βHSD1 metabolizes the steroidal drug abiraterone to a competing agonist metabolite.","method":"Pharmacokinetic analysis of 7 steroidal abiraterone metabolites in healthy volunteers; serum metabolite quantification by genotype in patients treated with abiraterone acetate","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — pharmacokinetic study with direct metabolite measurement stratified by genotype, replicated mechanism","pmids":["29939161"],"is_preprint":false},{"year":2023,"finding":"Cancer-associated fibroblast (CAF)-secreted glucosamine increases O-GlcNAcylation in prostate cancer epithelial cells, elevating expression of the transcription factor Elk1, which then induces HSD3B1 transcription, upregulates 3βHSD1 enzymatic activity, and drives intratumoral androgen synthesis leading to castration-resistant prostate cancer. Genetic ablation of Elk1 in cancer epithelial cells suppressed CAF-induced androgen biosynthesis in vivo.","method":"Unbiased metabolomics, in vitro co-culture, Elk1 genetic ablation (in vivo), multiplex fluorescent imaging of patient samples","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including in vivo genetic ablation and patient tissue validation","pmids":["37009898"],"is_preprint":false},{"year":2023,"finding":"HSD3B1 in human placenta acts as an oxysterol 3β-hydroxysteroid dehydrogenase, catalyzing the conversion of Δ5-3β-hydroxy oxysterols (without a 7α-hydroxy group) to 3-oxo-4-ene oxysterols — a previously unrecognized enzymatic activity. Proof-of-principle experiments confirmed this activity in vitro. These 3-oxo-4-ene oxysterols were identified in umbilical cord blood and plasma of pregnant women, suggesting HSD3B1 controls oxysterol abundance delivered to the fetus.","method":"In vitro enzymatic assay with recombinant HSD3B1 and oxysterol substrates; mass spectrometry-based oxysterol identification in cord blood and maternal plasma","journal":"Open biology","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro reconstitution with recombinant enzyme, single study","pmids":["37132223"],"is_preprint":false},{"year":2023,"finding":"NR5A2 (LRH-1) is upregulated in darolutamide-resistant prostate cancer cells and is induced by darolutamide treatment and AR knockdown. NR5A2 acts as an upstream regulator inducing HSD3B1 expression; NR5A2 knockdown or pharmacological inhibition with ML180 decreased HSD3B1 and other steroidogenic enzyme expression, sensitizing cells to darolutamide. Loss of AR signaling thus triggers NR5A2/HSD3B1 pathway activation to sustain androgen synthesis.","method":"siRNA knockdown, pharmacological inhibition (ML180), drug resistance cell models, RT-PCR, Western blot","journal":"Drug resistance updates","confidence":"Medium","confidence_rationale":"Tier 2 — multiple genetic and pharmacological perturbations in single study","pmids":["37478518"],"is_preprint":false},{"year":2022,"finding":"VDR (vitamin D receptor) directly binds vitamin D response elements (VDREs) in the upstream region of the Hsd3b1 gene promoter and enhances its transcription, as confirmed by dual-luciferase reporter assay. VDR overexpression increased testosterone synthesis in mouse Leydig cells, with HSD3B1 overexpression also modulating lipid metabolism genes Lpl and Angptl4.","method":"Dual-luciferase reporter assay, RT-qPCR, Western blot, ELISA for testosterone, proteome analysis","journal":"Genes & genomics","confidence":"Medium","confidence_rationale":"Tier 2 — direct promoter binding confirmed by luciferase assay with VDREs, single study","pmids":["35254654"],"is_preprint":false},{"year":2022,"finding":"IL-4 induces HSD3B1 expression in HT-29 colon cancer cells via multiple signaling pathways: STAT6 binding to the HSD3B1 promoter, PI3K/AKT pathway, GSK3 (a downstream AKT target with stimulatory effect at late stages), and ERK1/2 and p38 MAPK pathways. IL-4 induction of HSD3B1 promoted steroid synthesis.","method":"STAT6 inhibitor, PI3K/AKT inhibitor, GSK3 inhibitor, MAPK inhibitors, promoter binding analysis, RT-PCR, Western blot","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pharmacological pathway dissections in single study","pmids":["36362361"],"is_preprint":false},{"year":2025,"finding":"LRH1 (liver receptor homolog-1/NR5A2) is a key transcriptional regulator of HSD3B1 in estrogen receptor-positive breast cancer. Long-term estrogen deprivation or tamoxifen treatment induces HSD3B1 expression and enzymatic activity. LRH1 inhibition suppressed HSD3B1 expression, DHEA metabolism to androstenedione, and ER target gene activation. HSD3B1 deficiency impaired DHEA-driven cell survival in endocrine-resistant cells.","method":"siRNA knockdown (HSD3B1 and LRH1), long-term estrogen deprivation model, tamoxifen-resistant cell model, RT-PCR, Western blot, metabolic assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — multiple genetic perturbations with mechanistic follow-up, single study","pmids":["40544998"],"is_preprint":false},{"year":2019,"finding":"The HSD3B1(1245C) missense variant encodes a 3βHSD1 protein that is resistant to ubiquitin-mediated degradation, resulting in higher steady-state protein levels and increased metabolic flux from adrenal DHEA/DHEA-sulfate to dihydrotestosterone in peripheral tissues and prostate cancer, thereby enabling castration-resistant prostate cancer development.","method":"Mechanistic summary established by prior biochemical studies referenced across multiple clinical cohort papers; the degradation-resistance mechanism is the stated mechanistic basis across the corpus","journal":"Endocrinology (review)","confidence":"High","confidence_rationale":"Tier 1–2 — mechanistic finding of ubiquitination resistance and protein stability consistently referenced as established biochemical mechanism across multiple independent labs and studies","pmids":["31271415","27575027","32565196"],"is_preprint":false},{"year":2018,"finding":"Estrogen receptor signaling (through estrogen receptors) mediates induction of Hsd3b1 mRNA in immature rat granulosa cells. An environmental estrogenic mixture increased Hsd3b1 expression, and addition of the estrogen receptor inhibitor ICI 182,780 prevented this increase, demonstrating ER-dependent transcriptional regulation of Hsd3b1.","method":"Pharmacological ER inhibition (ICI 182,780), RT-qPCR in primary granulosa cells","journal":"Journal of applied toxicology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological receptor inhibition with specific gene expression readout, single study","pmids":["29435998"],"is_preprint":false},{"year":2025,"finding":"Loss of GPR133 in prostate cancer cells transcriptionally upregulates HSD3B1, elevating intracellular testosterone levels and sustaining AR signaling despite enzalutamide treatment. siRNA-mediated silencing of HSD3B1 reversed enzalutamide resistance induced by GPR133 knockdown, placing HSD3B1 downstream of GPR133 in a resistance pathway.","method":"siRNA knockdown (GPR133 and HSD3B1), RNA sequencing, gain/loss-of-function in vitro, xenograft mouse model, testosterone measurement","journal":"The Prostate","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis via double knockdown rescue, in vivo validation, single study","pmids":["41664980"],"is_preprint":false}],"current_model":"HSD3B1 encodes 3β-hydroxysteroid dehydrogenase/Δ5→4 isomerase 1, which catalyzes the rate-limiting oxidative conversion of Δ5-3β-hydroxy steroids (including DHEA) to Δ4-3-keto steroids (including androstenedione) required for synthesis of all steroid hormone classes; a common missense variant (1245A>C, Thr367) renders the enzyme resistant to ubiquitin-mediated degradation, increasing protein stability and enhancing flux through the androgen synthesis pathway from adrenal precursors; HSD3B1 transcription is positively regulated by the androgen receptor itself (feed-forward), by GATA2, TEF-5, VDR, LRH1/NR5A2, and IL-4/STAT6/MAPK signaling, and is induced by cancer-associated fibroblast-secreted glucosamine via Elk1; additionally, 3βHSD1 metabolizes the steroidal drug abiraterone to an AR-agonist metabolite (3-keto-5α-abiraterone), and has an unexpected oxysterol 3β-dehydrogenase activity in placenta."},"narrative":{"teleology":[{"year":1989,"claim":"Establishing the foundational enzymatic identity of HSD3B1 resolved the molecular basis of the Δ5-to-Δ4 steroid conversion step required for all steroid hormone biosynthesis.","evidence":"Chromosomal mapping by in situ hybridization and prior biochemical characterization of 3βHSD activity","pmids":["2630193"],"confidence":"High","gaps":["No structural model of the enzyme","Tissue-specific isoform functions not yet dissected"]},{"year":2004,"claim":"Identification of a 53-bp distal enhancer with TEF-5 and GATA-binding sites explained how placenta-specific HSD3B1 expression is achieved, addressing how a ubiquitously needed steroidogenic step is tissue-restricted.","evidence":"Promoter deletion, EMSA, site-directed mutagenesis, and luciferase reporter assays in JEG-3 cells","pmids":["15131259"],"confidence":"High","gaps":["Identity of the GATA-like factor not fully resolved","Chromatin context and in vivo enhancer validation not performed"]},{"year":2017,"claim":"Demonstration that GATA2 activates and GATA3 represses HSD3B1 transcription via proximal promoter GATA elements revealed antagonistic transcriptional control in placenta, refining the earlier enhancer model.","evidence":"EMSA, ChIP, siRNA knockdown, and luciferase reporter assays in JEG-3 cells","pmids":["28655875"],"confidence":"High","gaps":["In vivo confirmation of GATA2/3 antagonism not shown","Whether GATA2/3 balance shifts in pathology unknown"]},{"year":2018,"claim":"Discovery that AR signaling transcriptionally induces HSD3B1, increasing DHEA-to-androstenedione flux, established a feed-forward loop in which androgen production self-amplifies—a critical insight for castration-resistant prostate cancer.","evidence":"RT-PCR, Western blot, enzalutamide blockade, castration xenograft models, and radiolabeled [³H]-DHEA metabolic flux assays in multiple prostate cancer cell lines","pmids":["29850791"],"confidence":"High","gaps":["Direct AR binding to HSD3B1 regulatory elements not demonstrated by ChIP","Kinetics of feed-forward saturation in vivo unresolved"]},{"year":2018,"claim":"Linking the HSD3B1(1245C) gain-of-function variant to abiraterone metabolism showed that 3βHSD1 converts the steroidal drug to an AR-agonist metabolite, revealing a pharmacogenomic mechanism of treatment resistance.","evidence":"Pharmacokinetic analysis of seven steroidal abiraterone metabolites in healthy volunteers and patients, stratified by HSD3B1 genotype","pmids":["29939161"],"confidence":"High","gaps":["Clinical outcome data tied to genotype-stratified metabolite levels limited","Whether co-administered drugs alter this conversion unknown"]},{"year":2019,"claim":"Establishing that the 1245C variant protein resists ubiquitin-mediated degradation provided the biochemical mechanism for the gain-of-function phenotype, explaining increased steady-state enzyme levels and enhanced peripheral androgen synthesis.","evidence":"Biochemical studies of protein stability and ubiquitination, referenced across multiple independent clinical cohort studies","pmids":["31271415","27575027","32565196"],"confidence":"High","gaps":["E3 ligase responsible for wild-type 3βHSD1 ubiquitination not identified","Structural basis of degradation resistance unknown"]},{"year":2022,"claim":"Demonstration that IL-4 induces HSD3B1 via STAT6 promoter binding plus PI3K/AKT and MAPK pathways in colon cancer cells extended the transcriptional regulatory network beyond reproductive tissues and into immune-cytokine signaling.","evidence":"STAT6, PI3K/AKT, GSK3, and MAPK pathway inhibitors combined with promoter analysis and RT-PCR/Western blot in HT-29 cells","pmids":["36362361"],"confidence":"Medium","gaps":["In vivo relevance in colon cancer not established","Direct STAT6 ChIP not shown","Single cell line used"]},{"year":2022,"claim":"Showing that VDR directly binds VDREs in the Hsd3b1 promoter to enhance transcription connected vitamin D signaling to steroidogenesis regulation.","evidence":"Dual-luciferase reporter assay, RT-qPCR, Western blot, and testosterone ELISA in mouse Leydig cells","pmids":["35254654"],"confidence":"Medium","gaps":["Only tested in mouse Leydig cells; human promoter confirmation needed","Physiological vitamin D concentration range not tested"]},{"year":2023,"claim":"Identifying cancer-associated fibroblast-secreted glucosamine as an inducer of HSD3B1 via O-GlcNAcylation/Elk1 revealed a microenvironment-driven mechanism for intratumoral androgen synthesis in castration-resistant prostate cancer.","evidence":"Unbiased metabolomics, co-culture, Elk1 genetic ablation in vivo, multiplex fluorescent imaging of patient tissues","pmids":["37009898"],"confidence":"High","gaps":["Whether Elk1 directly binds HSD3B1 promoter not confirmed by ChIP","Specificity of glucosamine effect versus other hexosamines untested"]},{"year":2023,"claim":"Demonstrating that 3βHSD1 catalyzes oxysterol 3β-dehydrogenation in placenta expanded the enzyme's substrate repertoire beyond classical steroids, implying a role in regulating oxysterol delivery to the fetus.","evidence":"In vitro enzymatic assay with recombinant HSD3B1 and oxysterol substrates; mass spectrometry identification of 3-oxo-4-ene oxysterols in cord blood and maternal plasma","pmids":["37132223"],"confidence":"Medium","gaps":["Physiological significance of placental oxysterol metabolism for fetal development unknown","Contribution relative to other oxysterol-metabolizing enzymes not quantified"]},{"year":2023,"claim":"Identification of NR5A2/LRH-1 as an upstream transcriptional inducer of HSD3B1 that is itself upregulated upon AR pathway blockade provided a bypass mechanism for sustained androgen synthesis during anti-androgen therapy.","evidence":"siRNA knockdown and ML180 pharmacological inhibition of NR5A2 in darolutamide-resistant prostate cancer cell models","pmids":["37478518"],"confidence":"Medium","gaps":["Direct NR5A2 binding to HSD3B1 promoter not confirmed by ChIP","In vivo therapeutic efficacy of NR5A2 inhibition not tested"]},{"year":2025,"claim":"Extending the NR5A2-HSD3B1 axis to ER-positive breast cancer showed that endocrine therapy-induced HSD3B1 upregulation enables DHEA-driven ER signaling, broadening the clinical relevance of this steroidogenic bypass beyond prostate cancer.","evidence":"siRNA knockdown of LRH1 and HSD3B1 in long-term estrogen-deprived and tamoxifen-resistant breast cancer cell models with metabolic assays","pmids":["40544998"],"confidence":"Medium","gaps":["Patient-derived validation not shown","Relative contribution of HSD3B1 versus aromatase in resistant tumors unclear"]},{"year":2025,"claim":"Placing HSD3B1 downstream of GPR133 loss demonstrated a new signaling axis: GPR133 deficiency de-represses HSD3B1 transcription, elevates intracellular testosterone, and sustains AR signaling through enzalutamide, with HSD3B1 knockdown rescuing sensitivity.","evidence":"Double siRNA knockdown epistasis, RNA-seq, xenograft models, testosterone quantification","pmids":["41664980"],"confidence":"Medium","gaps":["Mechanism of GPR133-mediated HSD3B1 repression unknown","Single study without independent replication"]},{"year":null,"claim":"Key unresolved questions include the identity of the E3 ubiquitin ligase targeting wild-type 3βHSD1, the structural basis of degradation resistance conferred by the Thr367 variant, whether direct AR or Elk1 binding to HSD3B1 regulatory regions occurs, and the in vivo physiological significance of placental oxysterol metabolism by this enzyme.","evidence":"","pmids":[],"confidence":"Low","gaps":["E3 ligase for 3βHSD1 not identified","No crystal structure of human 3βHSD1","In vivo contribution of oxysterol activity uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,4,6,11]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[4,11]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,4,6,11]},{"term_id":"R-HSA-9748784","term_label":"Drug ADME","supporting_discovery_ids":[4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,5,9]}],"complexes":[],"partners":["AR","GATA2","NR5A2","ELK1","VDR","TEAD1","GPR133"],"other_free_text":[]},"mechanistic_narrative":"HSD3B1 encodes 3β-hydroxysteroid dehydrogenase/Δ5→4 isomerase type 1, a rate-limiting enzyme that catalyzes the oxidative conversion of Δ5-3β-hydroxy steroids (e.g., DHEA, pregnenolone) to Δ4-3-keto steroids (e.g., androstenedione, progesterone), a step required for the biosynthesis of all steroid hormone classes [PMID:2630193]. A common missense variant (1245A>C, encoding Thr367) renders the enzyme resistant to ubiquitin-mediated degradation, increasing protein stability and metabolic flux from adrenal DHEA to dihydrotestosterone, thereby facilitating castration-resistant prostate cancer [PMID:31271415, PMID:27575027]. HSD3B1 transcription is regulated by a broad network of transcription factors—including AR (creating a feed-forward androgen synthesis loop), GATA2, TEF-5, NR5A2/LRH-1, VDR, Elk1 (induced by cancer-associated fibroblast-secreted glucosamine), and IL-4/STAT6/MAPK signaling—and its upregulation upon loss of AR signaling or endocrine therapy contributes to treatment resistance in both prostate and breast cancer [PMID:29850791, PMID:37009898, PMID:37478518, PMID:40544998]. Beyond classical steroidogenesis, 3βHSD1 also metabolizes the drug abiraterone to the AR-agonist metabolite 3-keto-5α-abiraterone and possesses oxysterol 3β-dehydrogenase activity in placenta [PMID:29939161, PMID:37132223]."},"prefetch_data":{"uniprot":{"accession":"P14060","full_name":"3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type 1","aliases":["3 beta-hydroxysteroid dehydrogenase/Delta 5-->4-isomerase type I","3-beta-HSD I","3-beta-hydroxy-5-ene steroid dehydrogenase","3-beta-hydroxy-Delta(5)-steroid dehydrogenase","3-beta-hydroxysteroid 3-dehydrogenase","Delta-5-3-ketosteroid isomerase","Dihydrotestosterone oxidoreductase","Steroid Delta-isomerase","Trophoblast antigen FDO161G"],"length_aa":373,"mass_kda":42.3,"function":"A bifunctional enzyme responsible for the oxidation and isomerization of 3beta-hydroxy-Delta(5)-steroid precursors to 3-oxo-Delta(4)-steroids, an essential step in steroid hormone biosynthesis. Specifically catalyzes the conversion of pregnenolone to progesterone, 17alpha-hydroxypregnenolone to 17alpha-hydroxyprogesterone, dehydroepiandrosterone (DHEA) to 4-androstenedione, and androstenediol to testosterone. Additionally, catalyzes the interconversion between 3beta-hydroxy and 3-oxo-5alpha-androstane steroids controlling the bioavalability of the active forms. Specifically converts dihydrotestosterone to its inactive form 5alpha-androstanediol, that does not bind androgen receptor/AR. Also converts androstanedione, a precursor of testosterone and estrone, to epiandrosterone (PubMed:1401999, PubMed:2139411). Expected to use NAD(+) as preferred electron donor for the 3beta-hydroxy-steroid dehydrogenase activity and NADPH for the 3-ketosteroid reductase activity (Probable)","subcellular_location":"Endoplasmic reticulum membrane; Mitochondrion membrane","url":"https://www.uniprot.org/uniprotkb/P14060/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HSD3B1","classification":"Not Classified","n_dependent_lines":49,"n_total_lines":1208,"dependency_fraction":0.04056291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HSD3B1","total_profiled":1310},"omim":[{"mim_id":"613890","title":"3-@BETA-HYDROXYSTEROID DEHYDROGENASE 2; HSD3B2","url":"https://www.omim.org/entry/613890"},{"mim_id":"201810","title":"ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 3-BETA-HYDROXYSTEROID DEHYDROGENASE 2 DEFICIENCY","url":"https://www.omim.org/entry/201810"},{"mim_id":"109715","title":"3-@BETA-HYDROXYSTEROID DEHYDROGENASE 1; HSD3B1","url":"https://www.omim.org/entry/109715"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoli","reliability":"Approved"},{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Primary cilium","reliability":"Approved"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Primary cilium transition zone","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"placenta","ntpm":73.1}],"url":"https://www.proteinatlas.org/search/HSD3B1"},"hgnc":{"alias_symbol":["SDR11E1"],"prev_symbol":["HSDB3","HSD3B"]},"alphafold":{"accession":"P14060","domains":[{"cath_id":"3.40.50.720","chopping":"5-269_324-357","consensus_level":"high","plddt":95.5377,"start":5,"end":357}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P14060","model_url":"https://alphafold.ebi.ac.uk/files/AF-P14060-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P14060-F1-predicted_aligned_error_v6.png","plddt_mean":94.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HSD3B1","jax_strain_url":"https://www.jax.org/strain/search?query=HSD3B1"},"sequence":{"accession":"P14060","fasta_url":"https://rest.uniprot.org/uniprotkb/P14060.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P14060/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P14060"}},"corpus_meta":[{"pmid":"19491374","id":"PMC_19491374","title":"Transcriptional regulation of steroidogenic genes: STARD1, CYP11A1 and HSD3B.","date":"2009","source":"Experimental biology and medicine (Maywood, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/19491374","citation_count":213,"is_preprint":false},{"pmid":"27575027","id":"PMC_27575027","title":"HSD3B1 and resistance to androgen-deprivation therapy in prostate cancer: a retrospective, multicohort study.","date":"2016","source":"The Lancet. 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catalyzes the oxidative conversion of Δ5-3β-hydroxy steroids to the Δ4-3-keto configuration, which is required for the biosynthesis of all classes of steroid hormones including progesterone, glucocorticoids, mineralocorticoids, androgens, and estrogens. The gene was chromosomally assigned to the p13 band of chromosome 1 by in situ hybridization.\",\n      \"method\": \"In situ hybridization with labeled HSD3B1-specific cDNA; enzymatic activity established by prior biochemical characterization\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — foundational enzymatic characterization replicated across many labs; chromosomal assignment confirmed by in situ hybridization\",\n      \"pmids\": [\"2630193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Placental-specific expression of HSD3B1 is determined by a 53-bp enhancer element located between -2570 and -2518 of the promoter, where TEF-5 (transcription enhancer factor-5) and a GATA-like protein coordinately bind two adjacent sites; site-specific mutations in either binding site completely abolished enhancer activity.\",\n      \"method\": \"Promoter deletion analysis, EMSA, site-directed mutagenesis, transfection of luciferase reporter constructs into JEG-3 cells\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods (EMSA, mutagenesis, reporter assays) in a single rigorous study\",\n      \"pmids\": [\"15131259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"GATA2 and GATA3 bind two GATA elements at -106/-99 and -52/-45 of the HSD3B1 proximal promoter. ChIP assays demonstrated GATA2 (but not GATA3) association with these regions in JEG-3 cells. GATA2 knockdown significantly reduced HSD3B1 expression, while GATA3 knockdown increased it, identifying GATA2 as a positive and GATA3 as a negative transcriptional regulator of HSD3B1 in human placenta.\",\n      \"method\": \"EMSA, ChIP assay, siRNA knockdown, luciferase reporter assay, Western blot\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (EMSA, ChIP, knockdown, reporter assay) in single study\",\n      \"pmids\": [\"28655875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Androgen receptor (AR) signaling transcriptionally induces HSD3B1 expression in prostate cancer cells (VCaP, CWR22Rv1, LNCaP, LAPC4) with peak induction at ~72 hours followed by attenuation at ~120 hours. Enzalutamide treatment abrogated androgen-induced HSD3B1 upregulation. In VCaP xenografts, castration reduced HSD3B1 expression in vivo. Androgen treatment increased metabolic flux from [3H]-DHEA to androstenedione, establishing a feed-forward loop of androgen synthesis.\",\n      \"method\": \"RT-PCR, Western blot, enzalutamide treatment (AR inhibition), in vivo xenograft castration model, radiolabeled substrate metabolic flux assay\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (transcriptional induction, protein levels, in vivo model, metabolic flux) in single study\",\n      \"pmids\": [\"29850791\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The HSD3B1(1245A>C) variant encodes a hyperactive 3βHSD1 protein (Thr367 variant) that increases metabolic flux from extragonadal precursor steroids (DHEA) to DHT synthesis in prostate cancer. Patients inheriting the 1245C variant have a stepwise increase in serum 3-keto-5α-abiraterone (an AR-stimulating abiraterone metabolite generated by 3βHSD1 action on abiraterone), demonstrating that 3βHSD1 metabolizes the steroidal drug abiraterone to a competing agonist metabolite.\",\n      \"method\": \"Pharmacokinetic analysis of 7 steroidal abiraterone metabolites in healthy volunteers; serum metabolite quantification by genotype in patients treated with abiraterone acetate\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — pharmacokinetic study with direct metabolite measurement stratified by genotype, replicated mechanism\",\n      \"pmids\": [\"29939161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cancer-associated fibroblast (CAF)-secreted glucosamine increases O-GlcNAcylation in prostate cancer epithelial cells, elevating expression of the transcription factor Elk1, which then induces HSD3B1 transcription, upregulates 3βHSD1 enzymatic activity, and drives intratumoral androgen synthesis leading to castration-resistant prostate cancer. Genetic ablation of Elk1 in cancer epithelial cells suppressed CAF-induced androgen biosynthesis in vivo.\",\n      \"method\": \"Unbiased metabolomics, in vitro co-culture, Elk1 genetic ablation (in vivo), multiplex fluorescent imaging of patient samples\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vivo genetic ablation and patient tissue validation\",\n      \"pmids\": [\"37009898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HSD3B1 in human placenta acts as an oxysterol 3β-hydroxysteroid dehydrogenase, catalyzing the conversion of Δ5-3β-hydroxy oxysterols (without a 7α-hydroxy group) to 3-oxo-4-ene oxysterols — a previously unrecognized enzymatic activity. Proof-of-principle experiments confirmed this activity in vitro. These 3-oxo-4-ene oxysterols were identified in umbilical cord blood and plasma of pregnant women, suggesting HSD3B1 controls oxysterol abundance delivered to the fetus.\",\n      \"method\": \"In vitro enzymatic assay with recombinant HSD3B1 and oxysterol substrates; mass spectrometry-based oxysterol identification in cord blood and maternal plasma\",\n      \"journal\": \"Open biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with recombinant enzyme, single study\",\n      \"pmids\": [\"37132223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NR5A2 (LRH-1) is upregulated in darolutamide-resistant prostate cancer cells and is induced by darolutamide treatment and AR knockdown. NR5A2 acts as an upstream regulator inducing HSD3B1 expression; NR5A2 knockdown or pharmacological inhibition with ML180 decreased HSD3B1 and other steroidogenic enzyme expression, sensitizing cells to darolutamide. Loss of AR signaling thus triggers NR5A2/HSD3B1 pathway activation to sustain androgen synthesis.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibition (ML180), drug resistance cell models, RT-PCR, Western blot\",\n      \"journal\": \"Drug resistance updates\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic and pharmacological perturbations in single study\",\n      \"pmids\": [\"37478518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"VDR (vitamin D receptor) directly binds vitamin D response elements (VDREs) in the upstream region of the Hsd3b1 gene promoter and enhances its transcription, as confirmed by dual-luciferase reporter assay. VDR overexpression increased testosterone synthesis in mouse Leydig cells, with HSD3B1 overexpression also modulating lipid metabolism genes Lpl and Angptl4.\",\n      \"method\": \"Dual-luciferase reporter assay, RT-qPCR, Western blot, ELISA for testosterone, proteome analysis\",\n      \"journal\": \"Genes & genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct promoter binding confirmed by luciferase assay with VDREs, single study\",\n      \"pmids\": [\"35254654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IL-4 induces HSD3B1 expression in HT-29 colon cancer cells via multiple signaling pathways: STAT6 binding to the HSD3B1 promoter, PI3K/AKT pathway, GSK3 (a downstream AKT target with stimulatory effect at late stages), and ERK1/2 and p38 MAPK pathways. IL-4 induction of HSD3B1 promoted steroid synthesis.\",\n      \"method\": \"STAT6 inhibitor, PI3K/AKT inhibitor, GSK3 inhibitor, MAPK inhibitors, promoter binding analysis, RT-PCR, Western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological pathway dissections in single study\",\n      \"pmids\": [\"36362361\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LRH1 (liver receptor homolog-1/NR5A2) is a key transcriptional regulator of HSD3B1 in estrogen receptor-positive breast cancer. Long-term estrogen deprivation or tamoxifen treatment induces HSD3B1 expression and enzymatic activity. LRH1 inhibition suppressed HSD3B1 expression, DHEA metabolism to androstenedione, and ER target gene activation. HSD3B1 deficiency impaired DHEA-driven cell survival in endocrine-resistant cells.\",\n      \"method\": \"siRNA knockdown (HSD3B1 and LRH1), long-term estrogen deprivation model, tamoxifen-resistant cell model, RT-PCR, Western blot, metabolic assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic perturbations with mechanistic follow-up, single study\",\n      \"pmids\": [\"40544998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The HSD3B1(1245C) missense variant encodes a 3βHSD1 protein that is resistant to ubiquitin-mediated degradation, resulting in higher steady-state protein levels and increased metabolic flux from adrenal DHEA/DHEA-sulfate to dihydrotestosterone in peripheral tissues and prostate cancer, thereby enabling castration-resistant prostate cancer development.\",\n      \"method\": \"Mechanistic summary established by prior biochemical studies referenced across multiple clinical cohort papers; the degradation-resistance mechanism is the stated mechanistic basis across the corpus\",\n      \"journal\": \"Endocrinology (review)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mechanistic finding of ubiquitination resistance and protein stability consistently referenced as established biochemical mechanism across multiple independent labs and studies\",\n      \"pmids\": [\"31271415\", \"27575027\", \"32565196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Estrogen receptor signaling (through estrogen receptors) mediates induction of Hsd3b1 mRNA in immature rat granulosa cells. An environmental estrogenic mixture increased Hsd3b1 expression, and addition of the estrogen receptor inhibitor ICI 182,780 prevented this increase, demonstrating ER-dependent transcriptional regulation of Hsd3b1.\",\n      \"method\": \"Pharmacological ER inhibition (ICI 182,780), RT-qPCR in primary granulosa cells\",\n      \"journal\": \"Journal of applied toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological receptor inhibition with specific gene expression readout, single study\",\n      \"pmids\": [\"29435998\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of GPR133 in prostate cancer cells transcriptionally upregulates HSD3B1, elevating intracellular testosterone levels and sustaining AR signaling despite enzalutamide treatment. siRNA-mediated silencing of HSD3B1 reversed enzalutamide resistance induced by GPR133 knockdown, placing HSD3B1 downstream of GPR133 in a resistance pathway.\",\n      \"method\": \"siRNA knockdown (GPR133 and HSD3B1), RNA sequencing, gain/loss-of-function in vitro, xenograft mouse model, testosterone measurement\",\n      \"journal\": \"The Prostate\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via double knockdown rescue, in vivo validation, single study\",\n      \"pmids\": [\"41664980\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HSD3B1 encodes 3β-hydroxysteroid dehydrogenase/Δ5→4 isomerase 1, which catalyzes the rate-limiting oxidative conversion of Δ5-3β-hydroxy steroids (including DHEA) to Δ4-3-keto steroids (including androstenedione) required for synthesis of all steroid hormone classes; a common missense variant (1245A>C, Thr367) renders the enzyme resistant to ubiquitin-mediated degradation, increasing protein stability and enhancing flux through the androgen synthesis pathway from adrenal precursors; HSD3B1 transcription is positively regulated by the androgen receptor itself (feed-forward), by GATA2, TEF-5, VDR, LRH1/NR5A2, and IL-4/STAT6/MAPK signaling, and is induced by cancer-associated fibroblast-secreted glucosamine via Elk1; additionally, 3βHSD1 metabolizes the steroidal drug abiraterone to an AR-agonist metabolite (3-keto-5α-abiraterone), and has an unexpected oxysterol 3β-dehydrogenase activity in placenta.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HSD3B1 encodes 3β-hydroxysteroid dehydrogenase/Δ5→4 isomerase type 1, a rate-limiting enzyme that catalyzes the oxidative conversion of Δ5-3β-hydroxy steroids (e.g., DHEA, pregnenolone) to Δ4-3-keto steroids (e.g., androstenedione, progesterone), a step required for the biosynthesis of all steroid hormone classes [PMID:2630193]. A common missense variant (1245A>C, encoding Thr367) renders the enzyme resistant to ubiquitin-mediated degradation, increasing protein stability and metabolic flux from adrenal DHEA to dihydrotestosterone, thereby facilitating castration-resistant prostate cancer [PMID:31271415, PMID:27575027]. HSD3B1 transcription is regulated by a broad network of transcription factors—including AR (creating a feed-forward androgen synthesis loop), GATA2, TEF-5, NR5A2/LRH-1, VDR, Elk1 (induced by cancer-associated fibroblast-secreted glucosamine), and IL-4/STAT6/MAPK signaling—and its upregulation upon loss of AR signaling or endocrine therapy contributes to treatment resistance in both prostate and breast cancer [PMID:29850791, PMID:37009898, PMID:37478518, PMID:40544998]. Beyond classical steroidogenesis, 3βHSD1 also metabolizes the drug abiraterone to the AR-agonist metabolite 3-keto-5α-abiraterone and possesses oxysterol 3β-dehydrogenase activity in placenta [PMID:29939161, PMID:37132223].\",\n  \"teleology\": [\n    {\n      \"year\": 1989,\n      \"claim\": \"Establishing the foundational enzymatic identity of HSD3B1 resolved the molecular basis of the Δ5-to-Δ4 steroid conversion step required for all steroid hormone biosynthesis.\",\n      \"evidence\": \"Chromosomal mapping by in situ hybridization and prior biochemical characterization of 3βHSD activity\",\n      \"pmids\": [\"2630193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the enzyme\", \"Tissue-specific isoform functions not yet dissected\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of a 53-bp distal enhancer with TEF-5 and GATA-binding sites explained how placenta-specific HSD3B1 expression is achieved, addressing how a ubiquitously needed steroidogenic step is tissue-restricted.\",\n      \"evidence\": \"Promoter deletion, EMSA, site-directed mutagenesis, and luciferase reporter assays in JEG-3 cells\",\n      \"pmids\": [\"15131259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the GATA-like factor not fully resolved\", \"Chromatin context and in vivo enhancer validation not performed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstration that GATA2 activates and GATA3 represses HSD3B1 transcription via proximal promoter GATA elements revealed antagonistic transcriptional control in placenta, refining the earlier enhancer model.\",\n      \"evidence\": \"EMSA, ChIP, siRNA knockdown, and luciferase reporter assays in JEG-3 cells\",\n      \"pmids\": [\"28655875\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo confirmation of GATA2/3 antagonism not shown\", \"Whether GATA2/3 balance shifts in pathology unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovery that AR signaling transcriptionally induces HSD3B1, increasing DHEA-to-androstenedione flux, established a feed-forward loop in which androgen production self-amplifies—a critical insight for castration-resistant prostate cancer.\",\n      \"evidence\": \"RT-PCR, Western blot, enzalutamide blockade, castration xenograft models, and radiolabeled [³H]-DHEA metabolic flux assays in multiple prostate cancer cell lines\",\n      \"pmids\": [\"29850791\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct AR binding to HSD3B1 regulatory elements not demonstrated by ChIP\", \"Kinetics of feed-forward saturation in vivo unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Linking the HSD3B1(1245C) gain-of-function variant to abiraterone metabolism showed that 3βHSD1 converts the steroidal drug to an AR-agonist metabolite, revealing a pharmacogenomic mechanism of treatment resistance.\",\n      \"evidence\": \"Pharmacokinetic analysis of seven steroidal abiraterone metabolites in healthy volunteers and patients, stratified by HSD3B1 genotype\",\n      \"pmids\": [\"29939161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Clinical outcome data tied to genotype-stratified metabolite levels limited\", \"Whether co-administered drugs alter this conversion unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing that the 1245C variant protein resists ubiquitin-mediated degradation provided the biochemical mechanism for the gain-of-function phenotype, explaining increased steady-state enzyme levels and enhanced peripheral androgen synthesis.\",\n      \"evidence\": \"Biochemical studies of protein stability and ubiquitination, referenced across multiple independent clinical cohort studies\",\n      \"pmids\": [\"31271415\", \"27575027\", \"32565196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E3 ligase responsible for wild-type 3βHSD1 ubiquitination not identified\", \"Structural basis of degradation resistance unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that IL-4 induces HSD3B1 via STAT6 promoter binding plus PI3K/AKT and MAPK pathways in colon cancer cells extended the transcriptional regulatory network beyond reproductive tissues and into immune-cytokine signaling.\",\n      \"evidence\": \"STAT6, PI3K/AKT, GSK3, and MAPK pathway inhibitors combined with promoter analysis and RT-PCR/Western blot in HT-29 cells\",\n      \"pmids\": [\"36362361\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance in colon cancer not established\", \"Direct STAT6 ChIP not shown\", \"Single cell line used\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showing that VDR directly binds VDREs in the Hsd3b1 promoter to enhance transcription connected vitamin D signaling to steroidogenesis regulation.\",\n      \"evidence\": \"Dual-luciferase reporter assay, RT-qPCR, Western blot, and testosterone ELISA in mouse Leydig cells\",\n      \"pmids\": [\"35254654\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only tested in mouse Leydig cells; human promoter confirmation needed\", \"Physiological vitamin D concentration range not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying cancer-associated fibroblast-secreted glucosamine as an inducer of HSD3B1 via O-GlcNAcylation/Elk1 revealed a microenvironment-driven mechanism for intratumoral androgen synthesis in castration-resistant prostate cancer.\",\n      \"evidence\": \"Unbiased metabolomics, co-culture, Elk1 genetic ablation in vivo, multiplex fluorescent imaging of patient tissues\",\n      \"pmids\": [\"37009898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Elk1 directly binds HSD3B1 promoter not confirmed by ChIP\", \"Specificity of glucosamine effect versus other hexosamines untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that 3βHSD1 catalyzes oxysterol 3β-dehydrogenation in placenta expanded the enzyme's substrate repertoire beyond classical steroids, implying a role in regulating oxysterol delivery to the fetus.\",\n      \"evidence\": \"In vitro enzymatic assay with recombinant HSD3B1 and oxysterol substrates; mass spectrometry identification of 3-oxo-4-ene oxysterols in cord blood and maternal plasma\",\n      \"pmids\": [\"37132223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological significance of placental oxysterol metabolism for fetal development unknown\", \"Contribution relative to other oxysterol-metabolizing enzymes not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identification of NR5A2/LRH-1 as an upstream transcriptional inducer of HSD3B1 that is itself upregulated upon AR pathway blockade provided a bypass mechanism for sustained androgen synthesis during anti-androgen therapy.\",\n      \"evidence\": \"siRNA knockdown and ML180 pharmacological inhibition of NR5A2 in darolutamide-resistant prostate cancer cell models\",\n      \"pmids\": [\"37478518\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct NR5A2 binding to HSD3B1 promoter not confirmed by ChIP\", \"In vivo therapeutic efficacy of NR5A2 inhibition not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extending the NR5A2-HSD3B1 axis to ER-positive breast cancer showed that endocrine therapy-induced HSD3B1 upregulation enables DHEA-driven ER signaling, broadening the clinical relevance of this steroidogenic bypass beyond prostate cancer.\",\n      \"evidence\": \"siRNA knockdown of LRH1 and HSD3B1 in long-term estrogen-deprived and tamoxifen-resistant breast cancer cell models with metabolic assays\",\n      \"pmids\": [\"40544998\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Patient-derived validation not shown\", \"Relative contribution of HSD3B1 versus aromatase in resistant tumors unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placing HSD3B1 downstream of GPR133 loss demonstrated a new signaling axis: GPR133 deficiency de-represses HSD3B1 transcription, elevates intracellular testosterone, and sustains AR signaling through enzalutamide, with HSD3B1 knockdown rescuing sensitivity.\",\n      \"evidence\": \"Double siRNA knockdown epistasis, RNA-seq, xenograft models, testosterone quantification\",\n      \"pmids\": [\"41664980\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of GPR133-mediated HSD3B1 repression unknown\", \"Single study without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the identity of the E3 ubiquitin ligase targeting wild-type 3βHSD1, the structural basis of degradation resistance conferred by the Thr367 variant, whether direct AR or Elk1 binding to HSD3B1 regulatory regions occurs, and the in vivo physiological significance of placental oxysterol metabolism by this enzyme.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"E3 ligase for 3βHSD1 not identified\", \"No crystal structure of human 3βHSD1\", \"In vivo contribution of oxysterol activity uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 4, 6, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [4, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 4, 6, 11]},\n      {\"term_id\": \"R-HSA-9748784\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 5, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"AR\",\n      \"GATA2\",\n      \"NR5A2\",\n      \"ELK1\",\n      \"VDR\",\n      \"TEAD1\",\n      \"GPR133\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}