{"gene":"HSD17B4","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":1995,"finding":"HSD17B4 encodes a novel 80 kDa human 17β-hydroxysteroid dehydrogenase (type IV, 736 amino acids) with three distinct domain regions: an N-terminal short-chain alcohol dehydrogenase domain with 17β-HSD activity, a central domain homologous to the bifunctional Candida tropicalis enzyme and yeast FOX2 (hydratase activity), and a C-terminal domain homologous to sterol carrier protein 2. When overexpressed in mammalian cells, it catalyzes a unidirectional oxidative 17β-HSD reaction (estradiol → estrone). mRNA is expressed in many tissues, highest in liver, heart, prostate, and testes.","method":"cDNA cloning, sequence homology analysis, overexpression in mammalian cells with enzymatic activity assay","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — original cloning paper with in vitro/cell-based enzymatic activity assay and domain architecture determination","pmids":["7487879"],"is_preprint":false},{"year":1999,"finding":"HSD17B4 is a multifunctional peroxisomal enzyme: the full 80 kDa protein and its N-terminal 32 kDa cleavage fragment (aa 1–323) both catalyze dehydrogenase reactions on steroids at C17 and on D-3-hydroxyacyl-CoA (but not L-stereoisomers); the central domain (aa 324–596) catalyzes 2-enoyl-acyl-CoA hydratase activity with high efficiency; and the C-terminal domain (aa 597–737) facilitates transfer of 7-dehydrocholesterol and phosphatidylcholine between membranes in vitro. The HSD17B4 gene is induced by progesterone and PPARα ligands (clofibrate) and repressed by phorbol esters. Loss-of-function mutations cause a fatal form of Zellweger syndrome.","method":"Biochemical domain dissection, in vitro enzymatic assays with truncated proteins, stereospecificity testing, lipid transfer assay, gene expression studies with pharmacological agents","journal":"Journal of molecular endocrinology","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal in vitro enzymatic assays with domain-specific truncation constructs, stereospecificity established","pmids":["10343282"],"is_preprint":false},{"year":2006,"finding":"HSD17B4 (D-bifunctional protein) is established as a core peroxisomal fatty acid β-oxidation enzyme with both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activities, acting on the D-stereoisomer of 3-hydroxyacyl-CoA intermediates. It is the mammalian multifunctional enzyme type 2 (MFE-2) required for oxidation of very-long-chain fatty acids, pristanic acid, and bile acid intermediates in peroxisomes.","method":"Biochemical characterization and review of peroxisomal enzyme activities; substrate specificity assays documented across the field","journal":"Annual review of biochemistry","confidence":"High","confidence_rationale":"Tier 1 — comprehensive biochemical review synthesizing multiple reconstitution and enzymatic studies; peroxisomal localization and pathway position well established","pmids":["16756494"],"is_preprint":false},{"year":2010,"finding":"Compound heterozygous mutations in HSD17B4 (p.Y217C in the dehydrogenase domain predicted by structural analysis to destabilize the domain, and p.Y568X causing very low transcript levels) cause Perrault syndrome (ovarian dysgenesis, sensorineural deafness, neurological manifestations). Expression of mutant HSD17B4 protein in the compound heterozygote was severely reduced, establishing that partial loss of HSD17B4 function underlies this milder phenotype overlapping with lethal DBP deficiency.","method":"Whole-exome sequencing, Sanger confirmation of variants, structural modeling of missense mutation, protein expression analysis in patient cells","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic + structural modeling + patient protein expression; establishes genotype-phenotype relationship for HSD17B4 mutations","pmids":["20673864"],"is_preprint":false},{"year":2012,"finding":"Compound heterozygous mutations spanning both the dehydrogenase domain (p.Ala34Val) and hydratase domain (p.Ile516Thr) of HSD17B4 define a novel type IV DBP deficiency. Fibroblast studies showed markedly reduced but detectable hydratase and dehydrogenase activities and reduced pristanic acid β-oxidation, with normal VLCFA levels, establishing that partial residual activity in both domains produces a distinct, mild, late-onset phenotype (sensorineural hearing loss, cerebellar and sensory ataxia).","method":"Exome sequencing, Sanger confirmation, fibroblast enzymatic activity assays (pristanic acid β-oxidation, hydratase activity, dehydrogenase activity), biochemical serum/urine analysis","journal":"Orphanet journal of rare diseases","confidence":"High","confidence_rationale":"Tier 1–2 — enzymatic activity directly measured in patient fibroblasts, domain-specific activities quantified, clear genotype-phenotype correlation","pmids":["23181892"],"is_preprint":false},{"year":2014,"finding":"A heterozygous 12 kb deletion of exons 10–13 of HSD17B4 compounded with a rare missense variant (p.A196V) causes adult-onset HSD17B4-deficiency in a male presenting with cerebellar ataxia, peripheral neuropathy, hearing loss, and azoospermia — the first reported male case with infertility. Mildly elevated pristanic:phytanic acid and arachidonic:docosahexaenoic acid ratios confirmed dysfunctional peroxisomal fatty acid oxidation.","method":"Targeted exome sequencing, computational CNV inference from exome data, Sanger confirmation, retrospective biochemical review (serum lipid ratios, muscle biopsy)","journal":"BMC medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic identification with biochemical confirmation of peroxisomal dysfunction; phenotypic expansion to male infertility","pmids":["24602372"],"is_preprint":false},{"year":2016,"finding":"Compound heterozygous mutations in HSD17B4 (one nonsense/deletion + one missense in each of three families) cause juvenile-onset D-bifunctional protein deficiency with slowly progressive cerebellar ataxia, sensorineural deafness, and hypergonadotropic hypogonadism, consolidating the phenotypic spectrum of HSD17B4-associated disease.","method":"Linkage analysis (SNP microarray), exome sequencing, clinical and MRI characterization across 5 patients from 3 families","journal":"Neurology. Genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic evidence across multiple families; phenotypic consolidation without new enzymatic data","pmids":["27790638"],"is_preprint":false},{"year":2017,"finding":"Estrone (E1) upregulates acetylation of HSD17B4 at lysine 669 (K669), promoting its degradation via chaperone-mediated autophagy (CMA). CREBBP acts as the acetyltransferase writer and SIRT3 as the deacetylase eraser controlling K669 acetylation. A K669 mutation that prevents acetylation blocks CMA-mediated degradation and confers migratory and invasive properties to MCF7 breast cancer cells upon E1 treatment. K669 acetylation level is inversely correlated with HSD17B4 protein level in human breast cancer tissues.","method":"Site-directed mutagenesis (K669), Co-IP of CREBBP and SIRT3 with HSD17B4, CMA assay, migration/invasion assays in MCF7 cells, IHC of breast cancer tissues, acetylation mass spectrometry","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 1–2 — mutagenesis of specific acetylation site, identified writer (CREBBP) and eraser (SIRT3) by Co-IP, functional consequence of acetylation on CMA degradation and cell behavior","pmids":["28296597"],"is_preprint":false},{"year":2017,"finding":"Cytisine-linked isoflavonoids (CLIFs) bind specifically to the C-terminus (SCP-2-like domain) of HSD17B4 and selectively inhibit its enoyl-CoA hydratase activity without affecting the D-3-hydroxyacyl-CoA dehydrogenase activity. This was demonstrated using a biotin-modified CLIF pull-down assay to identify HSD17B4 as the target, and confirmed with truncated HSD17B4 constructs. HSD17B4 knockdown inhibited prostate and colon cancer cell proliferation, supporting HSD17B4 as a druggable cancer target.","method":"Biotin-modified ligand pull-down/affinity capture, domain-specific truncation constructs, enzymatic activity assays (hydratase vs. dehydrogenase), siRNA knockdown with proliferation assay","journal":"Organic & biomolecular chemistry","confidence":"High","confidence_rationale":"Tier 1–2 — pull-down identifies binding domain, truncation constructs establish domain specificity, orthogonal enzymatic assays distinguish activity selectivity","pmids":["28868548"],"is_preprint":false},{"year":2018,"finding":"Of five alternative splice forms of HSD17B4, only isoform 2 encodes an enzyme capable of inactivating testosterone and dihydrotestosterone by oxidation to their 17-keto forms. Expression of isoform 2 is specifically suppressed during development of castration-resistant prostate cancer (CRPC) in patients. Genetic silencing of isoform 2 shifts the metabolic balance toward 17β-OH androgens (testosterone and DHT), stimulates androgen receptor (AR) signaling, and drives CRPC development.","method":"Alternative splice form cloning and enzymatic activity assays, patient tumor RNA analysis, genetic silencing of isoform 2 with androgen metabolite measurement (mass spectrometry), AR activity readouts","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1–2 — isoform-specific enzymatic activity directly assayed, genetic silencing with metabolite measurement, patient tumor data; multiple orthogonal methods","pmids":["29346776"],"is_preprint":false},{"year":2020,"finding":"Dihydrotestosterone (DHT) treatment increases HSD17B4 acetylation at K669, promoting its degradation via chaperone-mediated autophagy (CMA) in prostate cancer cells. SIRT3 directly interacts with HSD17B4 to inhibit its K669 acetylation and enhance protein stability, while CREBBP promotes K669 acetylation and HSD17B4 degradation. HSD17B4 knockdown suppressed PCa cell proliferation, migration, and invasion, while overexpression had opposite effects. K669 acetylation level was negatively correlated with HSD17B4 protein in prostate cancer tissues.","method":"Co-IP of SIRT3 and CREBBP with HSD17B4, site-directed mutagenesis (K669), CMA assay, siRNA knockdown and overexpression with proliferation/migration/invasion assays, IHC of prostate cancer tissues","journal":"Aging","confidence":"High","confidence_rationale":"Tier 1–2 — Co-IP identifies direct SIRT3–HSD17B4 interaction, mutagenesis validates K669 as functional acetylation site, functional phenotype confirmed; replicates and extends 2017 breast cancer finding in prostate cancer","pmids":["32678070"],"is_preprint":false},{"year":2020,"finding":"Four patients with HSD17B4 mutations (including biallelic mutations affecting the dehydrogenase domain) showed variable phenotypes including polymicrogyria, sensorineural hearing loss, seizures, adrenal insufficiency, and nystagmus. Normal VLCFA levels were found in two of three patients tested, demonstrating that normal peroxisomal biomarkers do not exclude HSD17B4/DBP deficiency.","method":"Whole exome sequencing, Sanger confirmation, peroxisomal β-oxidation assay, brain MRI, clinical characterization","journal":"Molecular genetics and metabolism reports","confidence":"Medium","confidence_rationale":"Tier 2 — genetic confirmation with biochemical testing; primarily phenotypic expansion but includes functional assay","pmids":["32904102"],"is_preprint":false}],"current_model":"HSD17B4 encodes a multifunctional peroxisomal enzyme (D-bifunctional protein/MFE-2) with three functional domains: an N-terminal SDR-family dehydrogenase domain that oxidizes D-3-hydroxyacyl-CoA intermediates and estradiol (with isoform 2 specifically inactivating testosterone/DHT), a central 2-enoyl-CoA hydratase domain essential for peroxisomal fatty acid β-oxidation, and a C-terminal SCP-2-like sterol transfer domain; protein stability is regulated by CREBBP-mediated acetylation at K669 (promoted by estrone or DHT) that targets HSD17B4 for chaperone-mediated autophagy degradation, which is counteracted by SIRT3-mediated deacetylation, and loss-of-function mutations across the dehydrogenase or hydratase domains cause a spectrum of disease ranging from lethal neonatal Zellweger-like syndrome to juvenile/adult-onset Perrault syndrome (ovarian dysgenesis, hearing loss, ataxia), while isoform 2-specific loss enables castration-resistant prostate cancer through failure to inactivate androgens."},"narrative":{"teleology":[{"year":1995,"claim":"Cloning of HSD17B4 established a new 80 kDa multidomain enzyme with N-terminal SDR-family 17β-HSD activity (estradiol → estrone), a central hydratase-homologous domain, and a C-terminal SCP-2-like domain, resolving the molecular identity of a previously uncharacterized oxidative 17β-hydroxysteroid dehydrogenase.","evidence":"cDNA cloning, sequence homology analysis, and overexpression in mammalian cells with enzymatic activity assays","pmids":["7487879"],"confidence":"High","gaps":["Hydratase and SCP-2 activities of individual domains were not biochemically tested","Subcellular localization not directly demonstrated in this study"]},{"year":1999,"claim":"Biochemical dissection of each domain proved that HSD17B4 is a bona fide trifunctional peroxisomal enzyme: the N-terminal fragment is a D-3-hydroxyacyl-CoA dehydrogenase (with strict D-stereospecificity), the central domain is a 2-enoyl-CoA hydratase, and the C-terminal SCP-2-like domain transfers sterols and phospholipids between membranes.","evidence":"In vitro enzymatic assays with truncated recombinant proteins, stereospecificity testing, lipid transfer assays","pmids":["10343282"],"confidence":"High","gaps":["Physiological significance of SCP-2-domain lipid transfer in vivo not tested","Relative contribution of HSD17B4 vs. L-bifunctional protein (HSD17B10) to total peroxisomal β-oxidation flux unresolved"]},{"year":2006,"claim":"The position of HSD17B4 as the principal D-specific MFE-2 in peroxisomal β-oxidation of very-long-chain fatty acids, pristanic acid, and bile acid intermediates was consolidated, establishing it as an essential node in peroxisomal lipid catabolism.","evidence":"Comprehensive biochemical review synthesizing substrate specificity studies across multiple laboratories","pmids":["16756494"],"confidence":"High","gaps":["Structural basis for D-stereoselectivity not resolved at atomic level at this time","Regulation of MFE-2 enzyme activity in vivo unclear"]},{"year":2010,"claim":"Identification of compound heterozygous HSD17B4 mutations in Perrault syndrome patients revealed that partial loss of function produces a milder phenotype (ovarian dysgenesis, hearing loss, neurological features) distinct from lethal neonatal DBP deficiency, establishing a genotype–phenotype continuum for HSD17B4 deficiency.","evidence":"Whole-exome sequencing, structural modeling of missense mutation (Y217C), protein expression analysis in patient cells","pmids":["20673864"],"confidence":"High","gaps":["Residual enzymatic activity of Y217C mutant not directly quantified","Whether ovarian dysgenesis is due to steroid or fatty acid metabolic defect not distinguished"]},{"year":2012,"claim":"Quantitation of residual hydratase and dehydrogenase activities in patient fibroblasts with mutations spanning both catalytic domains defined a new type IV DBP deficiency and directly correlated partial enzymatic loss with a mild, late-onset ataxia–deafness phenotype.","evidence":"Patient fibroblast enzymatic activity assays (pristanic acid β-oxidation, hydratase, dehydrogenase) with exome-confirmed compound heterozygous mutations","pmids":["23181892"],"confidence":"High","gaps":["Whether residual activity thresholds can predict disease severity remains untested prospectively","Tissue-specific consequences of partial loss not assessed"]},{"year":2014,"claim":"A male patient with HSD17B4 deficiency and azoospermia expanded the phenotypic spectrum to include male infertility, indicating that peroxisomal β-oxidation via HSD17B4 is required for spermatogenesis.","evidence":"Exome sequencing (12 kb deletion + missense), elevated pristanic:phytanic acid ratio confirming peroxisomal dysfunction","pmids":["24602372"],"confidence":"Medium","gaps":["Mechanistic link between HSD17B4 loss and spermatogenic failure not established","Single case report; prevalence of male infertility in HSD17B4 deficiency unclear"]},{"year":2017,"claim":"Discovery that CREBBP acetylates HSD17B4 at K669 to trigger chaperone-mediated autophagy degradation, counteracted by SIRT3 deacetylation, revealed a post-translational switch controlling HSD17B4 protein levels in response to steroid hormones (estrone, DHT).","evidence":"Site-directed mutagenesis of K669, Co-IP of CREBBP and SIRT3, CMA assays, migration/invasion assays in MCF7 cells, IHC of breast cancer tissues","pmids":["28296597"],"confidence":"High","gaps":["Whether K669 acetylation regulates catalytic activity directly, or only protein turnover, is not determined","Identity of the CMA receptor recognizing acetylated HSD17B4 not established"]},{"year":2017,"claim":"Cytisine-linked isoflavonoids selectively bind the SCP-2-like C-terminal domain and inhibit hydratase (but not dehydrogenase) activity, establishing domain-selective pharmacological targeting of HSD17B4.","evidence":"Biotin-modified ligand pull-down, domain-specific truncation constructs, separate enzymatic assays for hydratase vs. dehydrogenase, siRNA knockdown proliferation assays","pmids":["28868548"],"confidence":"High","gaps":["Mechanism by which C-terminal binding allosterically inhibits the central hydratase domain is unknown","In vivo pharmacokinetics and selectivity not assessed"]},{"year":2018,"claim":"Isoform-specific analysis resolved a long-standing question about HSD17B4's androgen role: only isoform 2 catalyzes inactivation of testosterone and DHT, and its selective suppression in castration-resistant prostate cancer shifts the androgen metabolic balance toward active 17β-OH forms driving AR signaling.","evidence":"Splice form cloning with isoform-specific enzymatic assays, patient tumor RNA analysis, genetic silencing with LC-MS androgen metabolite quantification, AR activity readouts","pmids":["29346776"],"confidence":"High","gaps":["Mechanism of isoform 2 splicing regulation during CRPC progression not identified","Whether restoring isoform 2 can reverse CRPC in vivo is untested"]},{"year":2020,"claim":"Replication of the K669 acetylation–CMA degradation axis in prostate cancer cells confirmed it as a general regulatory mechanism across hormone-responsive tissues, and demonstrated that HSD17B4 protein levels directly modulate cancer cell proliferation, migration, and invasion.","evidence":"Co-IP, K669 mutagenesis, CMA assays, siRNA knockdown and overexpression phenotyping, IHC in prostate cancer tissues","pmids":["32678070"],"confidence":"High","gaps":["Relative contribution of HSD17B4's β-oxidation vs. steroid-metabolizing activities to cancer cell phenotypes not deconvolved","In vivo tumor model validation absent"]},{"year":null,"claim":"The structural basis for domain-selective catalysis (especially how C-terminal SCP-2 binding by small molecules inhibits the central hydratase domain), the mechanism coupling isoform 2 splicing to CRPC progression, and the tissue-specific determinants that distinguish lethal neonatal from adult-onset HSD17B4 deficiency remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length human HSD17B4 crystal structure capturing interdomain communication","Isoform 2 splicing regulators unidentified","Tissue-specific thresholds of residual activity needed to prevent organ-specific pathology unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,2,4,9]},{"term_id":"GO:0016853","term_label":"isomerase activity","supporting_discovery_ids":[1,2,4]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005777","term_label":"peroxisome","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2,4,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[3,9]}],"complexes":[],"partners":["CREBBP","SIRT3"],"other_free_text":[]},"mechanistic_narrative":"HSD17B4 encodes peroxisomal multifunctional enzyme type 2 (MFE-2/D-bifunctional protein), a tri-domain enzyme that catalyzes two sequential steps of peroxisomal fatty acid β-oxidation—2-enoyl-CoA hydratase and D-3-hydroxyacyl-CoA dehydrogenase activities—required for degradation of very-long-chain fatty acids, pristanic acid, and bile acid intermediates [PMID:16756494, PMID:10343282]. The N-terminal SDR-family dehydrogenase domain also oxidizes estradiol to estrone, and isoform 2 specifically inactivates testosterone and dihydrotestosterone; suppression of isoform 2 in prostate tumors shifts androgen metabolism toward active 17β-hydroxy forms and drives castration-resistant prostate cancer [PMID:29346776]. Protein stability is regulated by CREBBP-mediated acetylation at K669, which targets HSD17B4 for chaperone-mediated autophagy degradation and is counteracted by SIRT3-mediated deacetylation [PMID:28296597, PMID:32678070]. Biallelic loss-of-function mutations across the dehydrogenase and hydratase domains cause a phenotypic spectrum from lethal neonatal D-bifunctional protein deficiency to juvenile/adult-onset Perrault syndrome with cerebellar ataxia, sensorineural hearing loss, and hypergonadotropic hypogonadism [PMID:20673864, PMID:23181892]."},"prefetch_data":{"uniprot":{"accession":"P51659","full_name":"Peroxisomal multifunctional enzyme type 2","aliases":["17-beta-hydroxysteroid dehydrogenase 4","17-beta-HSD 4","D-bifunctional protein","DBP","Multifunctional protein 2","MFP-2","Short chain dehydrogenase/reductase family 8C member 1"],"length_aa":736,"mass_kda":79.7,"function":"Bifunctional enzyme acting on the peroxisomal fatty acid beta-oxidation pathway. Catalyzes two of the four reactions in fatty acid degradation: hydration of 2-enoyl-CoA (trans-2-enoyl-CoA) to produce (3R)-3-hydroxyacyl-CoA, and dehydrogenation of (3R)-3-hydroxyacyl-CoA to produce 3-ketoacyl-CoA (3-oxoacyl-CoA), which is further metabolized by SCPx. Can use straight-chain and branched-chain fatty acids, as well as bile acid intermediates as substrates","subcellular_location":"Peroxisome","url":"https://www.uniprot.org/uniprotkb/P51659/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HSD17B4","classification":"Not Classified","n_dependent_lines":60,"n_total_lines":1208,"dependency_fraction":0.04966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HSD17B4","total_profiled":1310},"omim":[{"mim_id":"620769","title":"HYDROXYACYL-THIOESTER DEHYDRATASE, TYPE 2; HTD2","url":"https://www.omim.org/entry/620769"},{"mim_id":"614129","title":"PERRAULT SYNDROME 3; PRLTS3","url":"https://www.omim.org/entry/614129"},{"mim_id":"609751","title":"ACYL-CoA OXIDASE 1, PALMITOYL; ACOX1","url":"https://www.omim.org/entry/609751"},{"mim_id":"607037","title":"ENOYL-CoA HYDRATASE/3-HYDROXYACYL CoA DEHYDROGENASE; EHHADH","url":"https://www.omim.org/entry/607037"},{"mim_id":"605573","title":"17-@BETA HYDROXYSTEROID DEHYDROGENASE III; HSD17B3","url":"https://www.omim.org/entry/605573"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Peroxisomes","reliability":"Enhanced"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":308.8}],"url":"https://www.proteinatlas.org/search/HSD17B4"},"hgnc":{"alias_symbol":["MFE-2","DBP","SDR8C1"],"prev_symbol":[]},"alphafold":{"accession":"P51659","domains":[{"cath_id":"3.40.50.720","chopping":"10-246","consensus_level":"high","plddt":96.9426,"start":10,"end":246},{"cath_id":"1.10.287.4290","chopping":"251-289","consensus_level":"medium","plddt":93.0741,"start":251,"end":289},{"cath_id":"3.10.129.10","chopping":"327-604","consensus_level":"medium","plddt":91.4217,"start":327,"end":604},{"cath_id":"3.30.1050.10","chopping":"622-733","consensus_level":"high","plddt":84.1113,"start":622,"end":733}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P51659","model_url":"https://alphafold.ebi.ac.uk/files/AF-P51659-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P51659-F1-predicted_aligned_error_v6.png","plddt_mean":89.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HSD17B4","jax_strain_url":"https://www.jax.org/strain/search?query=HSD17B4"},"sequence":{"accession":"P51659","fasta_url":"https://rest.uniprot.org/uniprotkb/P51659.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P51659/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P51659"}},"corpus_meta":[{"pmid":"23359474","id":"PMC_23359474","title":"Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutations.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23359474","citation_count":609,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16474407","id":"PMC_16474407","title":"Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions.","date":"2006","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/16474407","citation_count":467,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"16814730","id":"PMC_16814730","title":"The circadian PAR-domain basic leucine zipper transcription factors DBP, TEF, and HLF modulate basal and inducible xenobiotic detoxification.","date":"2006","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/16814730","citation_count":400,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"10733528","id":"PMC_10733528","title":"CLOCK, an essential pacemaker component, controls expression of the circadian transcription factor DBP.","date":"2000","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/10733528","citation_count":343,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24095930","id":"PMC_24095930","title":"Vitamin D and DBP: the free hormone hypothesis revisited.","date":"2013","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/24095930","citation_count":322,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"8405996","id":"PMC_8405996","title":"Circadian transcription of the cholesterol 7 alpha hydroxylase gene may involve the liver-enriched bZIP protein DBP.","date":"1993","source":"Genes & 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loss-of-function mutations (missense destabilizing the dehydrogenase domain + nonsense causing transcript loss) cause severely reduced HSD17B4 protein expression and underlie Perrault syndrome (ovarian dysgenesis, sensorineural deafness, ataxia), establishing HSD17B4 as the disease gene.\",\n      \"method\": \"Whole-exome sequencing, Sanger confirmation, structural prediction of missense effect, transcript and protein expression analysis in patient fibroblasts\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis/loss-of-function with defined molecular and clinical phenotype, supported by protein expression data; replicated across multiple families in subsequent studies\",\n      \"pmids\": [\"20673864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HSD17B4 encodes an 80 kDa peroxisomal protein with three functional domains: (1) an N-terminal dehydrogenase domain (aa 1–323, 32 kDa after cleavage) catalyzing oxidation of estradiol and D-3-hydroxyacyl-CoA (stereospecific for D-stereoisomers); (2) a central hydratase domain (aa 324–596) catalyzing 2-enoyl-acyl-CoA hydratase reaction; and (3) a C-terminal sterol carrier protein-2-like domain (aa 597–737) facilitating intermembrane transfer of 7-dehydrocholesterol and phosphatidylcholine. Mutations in HSD17B4 cause a fatal form of Zellweger syndrome.\",\n      \"method\": \"Biochemical activity assays with domain truncations, in vitro enzymatic characterization, stereoisomer specificity testing\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic reconstitution with truncation mutants defining each catalytic domain; multiple orthogonal assays\",\n      \"pmids\": [\"10343282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HSD17B4 protein stability is regulated by acetylation at lysine 669 (K669): estrone (E1) upregulates K669 acetylation, targeting HSD17B4 for degradation via chaperone-mediated autophagy (CMA). CREBBP acts as the acetyltransferase writer and SIRT3 acts as the deacetylase eraser at K669. K669 mutation (K669R) abolishes CMA-dependent degradation and confers migratory and invasive properties to MCF7 breast cancer cells upon E1 treatment.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, CMA assay, Western blot, cell migration/invasion assays, immunohistochemistry of human breast cancer tissues\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP identifying CREBBP and SIRT3, mutagenesis at K669, CMA assay, and functional cellular phenotype; multiple orthogonal methods in single study\",\n      \"pmids\": [\"28296597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Of five alternative splice forms of HSD17B4, only isoform 2 encodes a protein capable of inactivating testosterone and dihydrotestosterone (converting them to inert 17-keto steroids). Expression of isoform 2 is specifically suppressed during development of castration-resistant prostate cancer (CRPC). Genetic silencing of isoform 2 shifts metabolic balance toward 17β-OH androgens, stimulates androgen receptor signaling, and promotes CRPC development.\",\n      \"method\": \"Isoform-specific expression analysis in patient samples, enzymatic activity assays for each isoform, genetic silencing with defined androgen metabolite and AR activity readouts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — enzymatic characterization of each isoform combined with loss-of-function genetics and metabolite quantification; defined molecular mechanism linking isoform loss to CRPC\",\n      \"pmids\": [\"29346776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Acetylation at K669 of HSD17B4 promotes its CMA-dependent degradation; SIRT3 directly interacts with HSD17B4 to inhibit K669 acetylation and enhance its stability, while CREBBP promotes K669 acetylation and degradation. In prostate cancer tissues, HSD17B4 protein level is inversely correlated with K669 acetylation, and HSD17B4 knockdown suppresses PCa cell proliferation, migration, and invasion.\",\n      \"method\": \"Co-immunoprecipitation, site-directed mutagenesis, Western blot, knockdown/overexpression with cell proliferation and migration readouts, IHC correlation in patient tissues\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, mutagenesis, CMA assay, functional cellular phenotypes; corroborates findings from PMID 28296597 in prostate cancer context\",\n      \"pmids\": [\"32678070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cytisine-linked isoflavonoids (CLIFs) inhibit HSD17B4 by specifically binding the C-terminal domain (sterol carrier protein-2-like domain) and selectively inhibiting enoyl-CoA hydratase activity but not D-3-hydroxyacyl-CoA dehydrogenase activity. A biotin-modified CLIF pull-down assay identified HSD17B4 as the cellular target; truncated domain constructs confirmed C-terminal binding.\",\n      \"method\": \"Biotin-modified ligand pull-down assay, enzymatic activity assays with domain truncations, cancer cell proliferation assay with HSD17B4 knockdown\",\n      \"journal\": \"Organic & biomolecular chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pull-down with domain mapping and enzymatic activity assays; single lab, moderate number of orthogonal methods\",\n      \"pmids\": [\"28868548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Compound heterozygous mutations affecting both the dehydrogenase domain (c.101C>T; p.Ala34Val) and hydratase domain (c.1547T>C; p.Ile516Thr) of HSD17B4 define a novel type IV DBP deficiency; fibroblast studies confirmed markedly decreased but detectable hydratase and dehydrogenase enzymatic activities with normal VLCFA levels, indicating partial residual function of both domains.\",\n      \"method\": \"Exome sequencing, Sanger confirmation, fibroblast enzymatic activity assays (hydratase and dehydrogenase), peroxisomal beta-oxidation assay\",\n      \"journal\": \"Orphanet journal of rare diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct enzymatic activity measurement in patient fibroblasts plus genetic confirmation; orthogonal biochemical and genetic methods\",\n      \"pmids\": [\"23181892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Compound heterozygous mutations in HSD17B4 (heterozygous 12 kb deletion of exons 10–13 plus missense p.A196V) cause adult-onset peroxisomal D-bifunctional protein deficiency presenting as cerebellar ataxia, peripheral neuropathy, hearing loss, and azoospermia, expanding the phenotypic spectrum to include male infertility; retrospective biochemical review showed mildly elevated pristanic:phytanic acid ratio consistent with dysfunctional peroxisomal fatty acid oxidation.\",\n      \"method\": \"Targeted exome sequencing, CNV detection from exome data, Sanger confirmation, serum/urine/muscle biopsy biochemistry\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic identification plus biochemical peroxisomal assay; single case but orthogonal genetic and biochemical methods\",\n      \"pmids\": [\"24602372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Compound heterozygous mutations in HSD17B4 (one nonsense/deletion + one missense per family) cause juvenile D-bifunctional protein deficiency characterized by slowly progressive cerebellar ataxia, sensorineural deafness, and hypergonadotropic hypogonadism, confirmed in 5 patients from 3 families.\",\n      \"method\": \"Linkage analysis, exome sequencing, Sanger confirmation, clinical biochemistry\",\n      \"journal\": \"Neurology. Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined clinical phenotype replicated across 3 independent families\",\n      \"pmids\": [\"27790638\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HSD17B4 encodes a multifunctional peroxisomal enzyme (D-bifunctional protein) with three catalytic domains: an N-terminal D-3-hydroxyacyl-CoA dehydrogenase/17β-HSD domain that oxidizes estradiol and D-hydroxyacyl-CoA substrates, a central 2-enoyl-acyl-CoA hydratase domain essential for peroxisomal fatty acid beta-oxidation, and a C-terminal sterol carrier protein-2-like domain; protein stability is dynamically regulated by CREBBP-mediated acetylation at K669 (promoting chaperone-mediated autophagy degradation) and SIRT3-mediated deacetylation (stabilizing the protein), and an isoform-specific (isoform 2) androgen-inactivating function is selectively lost in castration-resistant prostate cancer, while loss-of-function mutations across domains cause peroxisomal disease ranging from lethal neonatal Zellweger syndrome to milder juvenile Perrault syndrome.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper and extract discoveries only from KEEP papers.\n\n**Classification:**\n\nPapers clearly about HSD17B4 (canonical peroxisomal D-bifunctional protein):\n- PMID 20673864 (Pierce 2010) — KEEP\n- PMID 10343282 (de Launoit 1999) — KEEP\n- PMID 23181892 (McMillan 2012) — KEEP\n- PMID 28296597 (Zhang 2017) — KEEP\n- PMID 29346776 (Ko 2018) — KEEP\n- PMID 24602372 (Lieber 2014) — KEEP\n- PMID 32678070 (Huang 2020) — KEEP\n- PMID 28868548 (Frasinyuk 2017) — KEEP\n- PMID 7487879 (Adamski 1995) — KEEP\n- PMID 16756494 (Wanders 2006) — KEEP (biochemistry review with mechanistic content on HSD17B4)\n- PMID 27790638 (Amor 2016) — KEEP\n- PMID 32904102 (Landau 2020) — KEEP\n- PMID 19027726 (Persson 2008) — KEEP (SDR nomenclature, mentions HSD17B4)\n- PMID 29050221 (Xu 2017) — expression/correlation, EXCLUDE\n- PMID 28186977 (Fujii 2017) — methylation biomarker, EXCLUDE\n- PMID 32968149 (Yamashita 2020) — methylation biomarker, EXCLUDE\n\nAll \"DBP\" papers about circadian transcription factor DBP (albumin D-site binding protein), Plasmodium vivax DBP (Duffy binding protein), vitamin D binding protein DBP, dibutyl phthalate (DBP), or other non-HSD17B4 entities — EXCLUDE.\n\nAll curated papers about proteomics/interactome/cDNA collections — EXCLUDE unless they provide specific mechanistic findings about HSD17B4.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1995,\n      \"finding\": \"HSD17B4 encodes a novel 80 kDa human 17β-hydroxysteroid dehydrogenase (type IV, 736 amino acids) with three distinct domain regions: an N-terminal short-chain alcohol dehydrogenase domain with 17β-HSD activity, a central domain homologous to the bifunctional Candida tropicalis enzyme and yeast FOX2 (hydratase activity), and a C-terminal domain homologous to sterol carrier protein 2. When overexpressed in mammalian cells, it catalyzes a unidirectional oxidative 17β-HSD reaction (estradiol → estrone). mRNA is expressed in many tissues, highest in liver, heart, prostate, and testes.\",\n      \"method\": \"cDNA cloning, sequence homology analysis, overexpression in mammalian cells with enzymatic activity assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original cloning paper with in vitro/cell-based enzymatic activity assay and domain architecture determination\",\n      \"pmids\": [\"7487879\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"HSD17B4 is a multifunctional peroxisomal enzyme: the full 80 kDa protein and its N-terminal 32 kDa cleavage fragment (aa 1–323) both catalyze dehydrogenase reactions on steroids at C17 and on D-3-hydroxyacyl-CoA (but not L-stereoisomers); the central domain (aa 324–596) catalyzes 2-enoyl-acyl-CoA hydratase activity with high efficiency; and the C-terminal domain (aa 597–737) facilitates transfer of 7-dehydrocholesterol and phosphatidylcholine between membranes in vitro. The HSD17B4 gene is induced by progesterone and PPARα ligands (clofibrate) and repressed by phorbol esters. Loss-of-function mutations cause a fatal form of Zellweger syndrome.\",\n      \"method\": \"Biochemical domain dissection, in vitro enzymatic assays with truncated proteins, stereospecificity testing, lipid transfer assay, gene expression studies with pharmacological agents\",\n      \"journal\": \"Journal of molecular endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal in vitro enzymatic assays with domain-specific truncation constructs, stereospecificity established\",\n      \"pmids\": [\"10343282\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HSD17B4 (D-bifunctional protein) is established as a core peroxisomal fatty acid β-oxidation enzyme with both 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activities, acting on the D-stereoisomer of 3-hydroxyacyl-CoA intermediates. It is the mammalian multifunctional enzyme type 2 (MFE-2) required for oxidation of very-long-chain fatty acids, pristanic acid, and bile acid intermediates in peroxisomes.\",\n      \"method\": \"Biochemical characterization and review of peroxisomal enzyme activities; substrate specificity assays documented across the field\",\n      \"journal\": \"Annual review of biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — comprehensive biochemical review synthesizing multiple reconstitution and enzymatic studies; peroxisomal localization and pathway position well established\",\n      \"pmids\": [\"16756494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Compound heterozygous mutations in HSD17B4 (p.Y217C in the dehydrogenase domain predicted by structural analysis to destabilize the domain, and p.Y568X causing very low transcript levels) cause Perrault syndrome (ovarian dysgenesis, sensorineural deafness, neurological manifestations). Expression of mutant HSD17B4 protein in the compound heterozygote was severely reduced, establishing that partial loss of HSD17B4 function underlies this milder phenotype overlapping with lethal DBP deficiency.\",\n      \"method\": \"Whole-exome sequencing, Sanger confirmation of variants, structural modeling of missense mutation, protein expression analysis in patient cells\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic + structural modeling + patient protein expression; establishes genotype-phenotype relationship for HSD17B4 mutations\",\n      \"pmids\": [\"20673864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Compound heterozygous mutations spanning both the dehydrogenase domain (p.Ala34Val) and hydratase domain (p.Ile516Thr) of HSD17B4 define a novel type IV DBP deficiency. Fibroblast studies showed markedly reduced but detectable hydratase and dehydrogenase activities and reduced pristanic acid β-oxidation, with normal VLCFA levels, establishing that partial residual activity in both domains produces a distinct, mild, late-onset phenotype (sensorineural hearing loss, cerebellar and sensory ataxia).\",\n      \"method\": \"Exome sequencing, Sanger confirmation, fibroblast enzymatic activity assays (pristanic acid β-oxidation, hydratase activity, dehydrogenase activity), biochemical serum/urine analysis\",\n      \"journal\": \"Orphanet journal of rare diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — enzymatic activity directly measured in patient fibroblasts, domain-specific activities quantified, clear genotype-phenotype correlation\",\n      \"pmids\": [\"23181892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A heterozygous 12 kb deletion of exons 10–13 of HSD17B4 compounded with a rare missense variant (p.A196V) causes adult-onset HSD17B4-deficiency in a male presenting with cerebellar ataxia, peripheral neuropathy, hearing loss, and azoospermia — the first reported male case with infertility. Mildly elevated pristanic:phytanic acid and arachidonic:docosahexaenoic acid ratios confirmed dysfunctional peroxisomal fatty acid oxidation.\",\n      \"method\": \"Targeted exome sequencing, computational CNV inference from exome data, Sanger confirmation, retrospective biochemical review (serum lipid ratios, muscle biopsy)\",\n      \"journal\": \"BMC medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic identification with biochemical confirmation of peroxisomal dysfunction; phenotypic expansion to male infertility\",\n      \"pmids\": [\"24602372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Compound heterozygous mutations in HSD17B4 (one nonsense/deletion + one missense in each of three families) cause juvenile-onset D-bifunctional protein deficiency with slowly progressive cerebellar ataxia, sensorineural deafness, and hypergonadotropic hypogonadism, consolidating the phenotypic spectrum of HSD17B4-associated disease.\",\n      \"method\": \"Linkage analysis (SNP microarray), exome sequencing, clinical and MRI characterization across 5 patients from 3 families\",\n      \"journal\": \"Neurology. Genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic evidence across multiple families; phenotypic consolidation without new enzymatic data\",\n      \"pmids\": [\"27790638\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Estrone (E1) upregulates acetylation of HSD17B4 at lysine 669 (K669), promoting its degradation via chaperone-mediated autophagy (CMA). CREBBP acts as the acetyltransferase writer and SIRT3 as the deacetylase eraser controlling K669 acetylation. A K669 mutation that prevents acetylation blocks CMA-mediated degradation and confers migratory and invasive properties to MCF7 breast cancer cells upon E1 treatment. K669 acetylation level is inversely correlated with HSD17B4 protein level in human breast cancer tissues.\",\n      \"method\": \"Site-directed mutagenesis (K669), Co-IP of CREBBP and SIRT3 with HSD17B4, CMA assay, migration/invasion assays in MCF7 cells, IHC of breast cancer tissues, acetylation mass spectrometry\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — mutagenesis of specific acetylation site, identified writer (CREBBP) and eraser (SIRT3) by Co-IP, functional consequence of acetylation on CMA degradation and cell behavior\",\n      \"pmids\": [\"28296597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cytisine-linked isoflavonoids (CLIFs) bind specifically to the C-terminus (SCP-2-like domain) of HSD17B4 and selectively inhibit its enoyl-CoA hydratase activity without affecting the D-3-hydroxyacyl-CoA dehydrogenase activity. This was demonstrated using a biotin-modified CLIF pull-down assay to identify HSD17B4 as the target, and confirmed with truncated HSD17B4 constructs. HSD17B4 knockdown inhibited prostate and colon cancer cell proliferation, supporting HSD17B4 as a druggable cancer target.\",\n      \"method\": \"Biotin-modified ligand pull-down/affinity capture, domain-specific truncation constructs, enzymatic activity assays (hydratase vs. dehydrogenase), siRNA knockdown with proliferation assay\",\n      \"journal\": \"Organic & biomolecular chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — pull-down identifies binding domain, truncation constructs establish domain specificity, orthogonal enzymatic assays distinguish activity selectivity\",\n      \"pmids\": [\"28868548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Of five alternative splice forms of HSD17B4, only isoform 2 encodes an enzyme capable of inactivating testosterone and dihydrotestosterone by oxidation to their 17-keto forms. Expression of isoform 2 is specifically suppressed during development of castration-resistant prostate cancer (CRPC) in patients. Genetic silencing of isoform 2 shifts the metabolic balance toward 17β-OH androgens (testosterone and DHT), stimulates androgen receptor (AR) signaling, and drives CRPC development.\",\n      \"method\": \"Alternative splice form cloning and enzymatic activity assays, patient tumor RNA analysis, genetic silencing of isoform 2 with androgen metabolite measurement (mass spectrometry), AR activity readouts\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — isoform-specific enzymatic activity directly assayed, genetic silencing with metabolite measurement, patient tumor data; multiple orthogonal methods\",\n      \"pmids\": [\"29346776\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Dihydrotestosterone (DHT) treatment increases HSD17B4 acetylation at K669, promoting its degradation via chaperone-mediated autophagy (CMA) in prostate cancer cells. SIRT3 directly interacts with HSD17B4 to inhibit its K669 acetylation and enhance protein stability, while CREBBP promotes K669 acetylation and HSD17B4 degradation. HSD17B4 knockdown suppressed PCa cell proliferation, migration, and invasion, while overexpression had opposite effects. K669 acetylation level was negatively correlated with HSD17B4 protein in prostate cancer tissues.\",\n      \"method\": \"Co-IP of SIRT3 and CREBBP with HSD17B4, site-directed mutagenesis (K669), CMA assay, siRNA knockdown and overexpression with proliferation/migration/invasion assays, IHC of prostate cancer tissues\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — Co-IP identifies direct SIRT3–HSD17B4 interaction, mutagenesis validates K669 as functional acetylation site, functional phenotype confirmed; replicates and extends 2017 breast cancer finding in prostate cancer\",\n      \"pmids\": [\"32678070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Four patients with HSD17B4 mutations (including biallelic mutations affecting the dehydrogenase domain) showed variable phenotypes including polymicrogyria, sensorineural hearing loss, seizures, adrenal insufficiency, and nystagmus. Normal VLCFA levels were found in two of three patients tested, demonstrating that normal peroxisomal biomarkers do not exclude HSD17B4/DBP deficiency.\",\n      \"method\": \"Whole exome sequencing, Sanger confirmation, peroxisomal β-oxidation assay, brain MRI, clinical characterization\",\n      \"journal\": \"Molecular genetics and metabolism reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic confirmation with biochemical testing; primarily phenotypic expansion but includes functional assay\",\n      \"pmids\": [\"32904102\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HSD17B4 encodes a multifunctional peroxisomal enzyme (D-bifunctional protein/MFE-2) with three functional domains: an N-terminal SDR-family dehydrogenase domain that oxidizes D-3-hydroxyacyl-CoA intermediates and estradiol (with isoform 2 specifically inactivating testosterone/DHT), a central 2-enoyl-CoA hydratase domain essential for peroxisomal fatty acid β-oxidation, and a C-terminal SCP-2-like sterol transfer domain; protein stability is regulated by CREBBP-mediated acetylation at K669 (promoted by estrone or DHT) that targets HSD17B4 for chaperone-mediated autophagy degradation, which is counteracted by SIRT3-mediated deacetylation, and loss-of-function mutations across the dehydrogenase or hydratase domains cause a spectrum of disease ranging from lethal neonatal Zellweger-like syndrome to juvenile/adult-onset Perrault syndrome (ovarian dysgenesis, hearing loss, ataxia), while isoform 2-specific loss enables castration-resistant prostate cancer through failure to inactivate androgens.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"HSD17B4 encodes the peroxisomal D-bifunctional protein (DBP), a multifunctional enzyme central to peroxisomal fatty acid β-oxidation and steroid metabolism. The 80 kDa precursor contains three functional domains: an N-terminal D-3-hydroxyacyl-CoA dehydrogenase domain that oxidizes estradiol and D-stereoisomer hydroxyacyl-CoA substrates, a central 2-enoyl-acyl-CoA hydratase domain, and a C-terminal sterol carrier protein-2-like domain that mediates intermembrane lipid transfer [PMID:10343282]; among five splice isoforms, only isoform 2 catalyzes androgen inactivation, and its selective loss in castration-resistant prostate cancer shifts metabolic balance toward active androgens and sustains androgen receptor signaling [PMID:29346776]. Protein stability is dynamically regulated by CREBBP-mediated acetylation at K669, which targets HSD17B4 for chaperone-mediated autophagy degradation, opposed by SIRT3-mediated deacetylation that stabilizes the protein [PMID:28296597, PMID:32678070]. Loss-of-function mutations across HSD17B4 domains cause a spectrum of peroxisomal disease, from lethal neonatal D-bifunctional protein deficiency (Zellweger-like) to milder juvenile presentations including Perrault syndrome with ovarian dysgenesis, sensorineural deafness, and cerebellar ataxia [PMID:20673864, PMID:23181892, PMID:27790638].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Defining the three-domain architecture of HSD17B4 resolved how a single peroxisomal protein performs dehydrogenase, hydratase, and lipid-transfer reactions with D-stereospecificity, establishing the biochemical basis for its multifunctionality.\",\n      \"evidence\": \"In vitro enzymatic assays with domain truncation constructs measuring substrate specificity and stereoisomer selectivity\",\n      \"pmids\": [\"10343282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model at atomic resolution for interdomain communication\",\n        \"Mechanism of C-terminal domain contribution to hydratase activity not resolved\",\n        \"Relative contribution of each domain to in vivo peroxisomal β-oxidation flux unknown\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of compound heterozygous HSD17B4 mutations in Perrault syndrome families established that partial loss of D-bifunctional protein function causes a distinct gonadal-neurological syndrome rather than lethal neonatal disease, revealing genotype-severity correlations.\",\n      \"evidence\": \"Whole-exome sequencing with Sanger validation, protein expression analysis in patient fibroblasts, structural prediction of missense impact\",\n      \"pmids\": [\"20673864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism linking partial DBP deficiency specifically to ovarian dysgenesis unknown\",\n        \"Threshold of residual enzymatic activity separating lethal from milder phenotypes not quantified\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Discovery of mutations affecting both the dehydrogenase and hydratase domains simultaneously (type IV DBP deficiency) demonstrated that partial residual activity of both catalytic domains can sustain near-normal very-long-chain fatty acid levels, explaining survival beyond infancy.\",\n      \"evidence\": \"Exome sequencing plus fibroblast enzymatic activity assays for both hydratase and dehydrogenase functions and peroxisomal β-oxidation flux measurement\",\n      \"pmids\": [\"23181892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Quantitative relationship between residual enzyme activity and disease severity across all deficiency types not established\",\n        \"Role of compensatory L-bifunctional protein in partial deficiency states not assessed\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Extension of the HSD17B4 disease spectrum to adult-onset cerebellar ataxia with azoospermia showed that even mild peroxisomal β-oxidation impairment (elevated pristanic:phytanic acid ratio) is pathogenic in cerebellum and testes over decades.\",\n      \"evidence\": \"Exome sequencing with CNV detection, serum biochemistry, muscle biopsy in a single adult patient\",\n      \"pmids\": [\"24602372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single case report; genotype–phenotype correlation requires larger cohort\",\n        \"Tissue-specific vulnerability of cerebellum and testes to mild DBP deficiency unexplained\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Replication of juvenile DBP deficiency across three independent families with compound heterozygous HSD17B4 mutations confirmed that slowly progressive cerebellar ataxia, deafness, and hypergonadotropic hypogonadism constitute a reproducible clinical entity distinct from neonatal Zellweger-spectrum disease.\",\n      \"evidence\": \"Linkage analysis, exome sequencing, Sanger confirmation in 5 patients from 3 families\",\n      \"pmids\": [\"27790638\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional enzymatic assays not performed in these families\",\n        \"Molecular basis of selective gonadal and cerebellar vulnerability still unresolved\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that CREBBP acetylates HSD17B4 at K669 and SIRT3 deacetylates it, with K669 acetylation targeting the protein for chaperone-mediated autophagy, revealed a regulated degradation pathway controlling HSD17B4 protein levels in response to estrone signaling.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, K669R site-directed mutagenesis, CMA assay, cell migration/invasion assays in MCF7 breast cancer cells\",\n      \"pmids\": [\"28296597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"CMA recognition motif around K669 not mapped\",\n        \"In vivo relevance of estrone-triggered degradation beyond breast cancer cells not tested\",\n        \"Whether K669 acetylation status affects enzymatic activity is unknown\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of HSD17B4 as the cellular target of cytisine-linked isoflavonoids, with binding at the C-terminal SCP-2-like domain selectively inhibiting hydratase but not dehydrogenase activity, demonstrated allosteric communication between the C-terminal and central domains.\",\n      \"evidence\": \"Biotin-modified ligand pull-down, enzymatic activity assays with domain truncations, cancer cell proliferation upon HSD17B4 knockdown\",\n      \"pmids\": [\"28868548\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Structural basis of allosteric inhibition not resolved\",\n        \"Specificity of CLIFs for HSD17B4 over other SCP-2 domain proteins not fully assessed\",\n        \"Single lab finding; independent replication lacking\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showing that only splice isoform 2 of HSD17B4 can inactivate testosterone and DHT, and that this isoform is selectively silenced in castration-resistant prostate cancer, established an isoform-specific androgen-inactivation mechanism whose loss drives CRPC.\",\n      \"evidence\": \"Isoform-specific expression profiling in patient tissues, enzymatic assays for all five isoforms, genetic silencing with quantification of androgen metabolites and AR target gene activity\",\n      \"pmids\": [\"29346776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism of isoform 2 selective silencing (epigenetic, transcriptional) not defined\",\n        \"Whether isoform 2 restoration is sufficient to reverse CRPC in vivo not tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Corroboration of the CREBBP/SIRT3–K669 acetylation axis in prostate cancer tissues, where HSD17B4 protein inversely correlates with K669 acetylation, extended the CMA-dependent degradation mechanism to a second cancer type and linked it to cell proliferation and invasion.\",\n      \"evidence\": \"Co-immunoprecipitation, K669 mutagenesis, knockdown/overexpression with proliferation and migration readouts, IHC in prostate cancer tissue arrays\",\n      \"pmids\": [\"32678070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Relative contribution of CMA-mediated degradation versus transcriptional regulation of HSD17B4 in prostate cancer not dissected\",\n        \"Whether SIRT3 regulation of HSD17B4 is direct in vivo or through intermediary complexes is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for interdomain communication (particularly how C-terminal domain engagement modulates hydratase activity), the tissue-specific mechanisms underlying selective cerebellar and gonadal vulnerability in partial DBP deficiency, and the epigenetic mechanism silencing isoform 2 in CRPC remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of full-length human HSD17B4 available\",\n        \"Tissue-specific compensatory role of L-bifunctional protein not delineated\",\n        \"Mechanism of isoform 2 selective silencing in CRPC undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [1, 3, 6]},\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [1, 5, 6]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [0, 1, 6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 3, 6, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CREBBP\",\n      \"SIRT3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"HSD17B4 encodes peroxisomal multifunctional enzyme type 2 (MFE-2/D-bifunctional protein), a tri-domain enzyme that catalyzes two sequential steps of peroxisomal fatty acid β-oxidation—2-enoyl-CoA hydratase and D-3-hydroxyacyl-CoA dehydrogenase activities—required for degradation of very-long-chain fatty acids, pristanic acid, and bile acid intermediates [PMID:16756494, PMID:10343282]. The N-terminal SDR-family dehydrogenase domain also oxidizes estradiol to estrone, and isoform 2 specifically inactivates testosterone and dihydrotestosterone; suppression of isoform 2 in prostate tumors shifts androgen metabolism toward active 17β-hydroxy forms and drives castration-resistant prostate cancer [PMID:29346776]. Protein stability is regulated by CREBBP-mediated acetylation at K669, which targets HSD17B4 for chaperone-mediated autophagy degradation and is counteracted by SIRT3-mediated deacetylation [PMID:28296597, PMID:32678070]. Biallelic loss-of-function mutations across the dehydrogenase and hydratase domains cause a phenotypic spectrum from lethal neonatal D-bifunctional protein deficiency to juvenile/adult-onset Perrault syndrome with cerebellar ataxia, sensorineural hearing loss, and hypergonadotropic hypogonadism [PMID:20673864, PMID:23181892].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Cloning of HSD17B4 established a new 80 kDa multidomain enzyme with N-terminal SDR-family 17β-HSD activity (estradiol → estrone), a central hydratase-homologous domain, and a C-terminal SCP-2-like domain, resolving the molecular identity of a previously uncharacterized oxidative 17β-hydroxysteroid dehydrogenase.\",\n      \"evidence\": \"cDNA cloning, sequence homology analysis, and overexpression in mammalian cells with enzymatic activity assays\",\n      \"pmids\": [\"7487879\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hydratase and SCP-2 activities of individual domains were not biochemically tested\", \"Subcellular localization not directly demonstrated in this study\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Biochemical dissection of each domain proved that HSD17B4 is a bona fide trifunctional peroxisomal enzyme: the N-terminal fragment is a D-3-hydroxyacyl-CoA dehydrogenase (with strict D-stereospecificity), the central domain is a 2-enoyl-CoA hydratase, and the C-terminal SCP-2-like domain transfers sterols and phospholipids between membranes.\",\n      \"evidence\": \"In vitro enzymatic assays with truncated recombinant proteins, stereospecificity testing, lipid transfer assays\",\n      \"pmids\": [\"10343282\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological significance of SCP-2-domain lipid transfer in vivo not tested\", \"Relative contribution of HSD17B4 vs. L-bifunctional protein (HSD17B10) to total peroxisomal β-oxidation flux unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"The position of HSD17B4 as the principal D-specific MFE-2 in peroxisomal β-oxidation of very-long-chain fatty acids, pristanic acid, and bile acid intermediates was consolidated, establishing it as an essential node in peroxisomal lipid catabolism.\",\n      \"evidence\": \"Comprehensive biochemical review synthesizing substrate specificity studies across multiple laboratories\",\n      \"pmids\": [\"16756494\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for D-stereoselectivity not resolved at atomic level at this time\", \"Regulation of MFE-2 enzyme activity in vivo unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of compound heterozygous HSD17B4 mutations in Perrault syndrome patients revealed that partial loss of function produces a milder phenotype (ovarian dysgenesis, hearing loss, neurological features) distinct from lethal neonatal DBP deficiency, establishing a genotype–phenotype continuum for HSD17B4 deficiency.\",\n      \"evidence\": \"Whole-exome sequencing, structural modeling of missense mutation (Y217C), protein expression analysis in patient cells\",\n      \"pmids\": [\"20673864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Residual enzymatic activity of Y217C mutant not directly quantified\", \"Whether ovarian dysgenesis is due to steroid or fatty acid metabolic defect not distinguished\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Quantitation of residual hydratase and dehydrogenase activities in patient fibroblasts with mutations spanning both catalytic domains defined a new type IV DBP deficiency and directly correlated partial enzymatic loss with a mild, late-onset ataxia–deafness phenotype.\",\n      \"evidence\": \"Patient fibroblast enzymatic activity assays (pristanic acid β-oxidation, hydratase, dehydrogenase) with exome-confirmed compound heterozygous mutations\",\n      \"pmids\": [\"23181892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether residual activity thresholds can predict disease severity remains untested prospectively\", \"Tissue-specific consequences of partial loss not assessed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A male patient with HSD17B4 deficiency and azoospermia expanded the phenotypic spectrum to include male infertility, indicating that peroxisomal β-oxidation via HSD17B4 is required for spermatogenesis.\",\n      \"evidence\": \"Exome sequencing (12 kb deletion + missense), elevated pristanic:phytanic acid ratio confirming peroxisomal dysfunction\",\n      \"pmids\": [\"24602372\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between HSD17B4 loss and spermatogenic failure not established\", \"Single case report; prevalence of male infertility in HSD17B4 deficiency unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Discovery that CREBBP acetylates HSD17B4 at K669 to trigger chaperone-mediated autophagy degradation, counteracted by SIRT3 deacetylation, revealed a post-translational switch controlling HSD17B4 protein levels in response to steroid hormones (estrone, DHT).\",\n      \"evidence\": \"Site-directed mutagenesis of K669, Co-IP of CREBBP and SIRT3, CMA assays, migration/invasion assays in MCF7 cells, IHC of breast cancer tissues\",\n      \"pmids\": [\"28296597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether K669 acetylation regulates catalytic activity directly, or only protein turnover, is not determined\", \"Identity of the CMA receptor recognizing acetylated HSD17B4 not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Cytisine-linked isoflavonoids selectively bind the SCP-2-like C-terminal domain and inhibit hydratase (but not dehydrogenase) activity, establishing domain-selective pharmacological targeting of HSD17B4.\",\n      \"evidence\": \"Biotin-modified ligand pull-down, domain-specific truncation constructs, separate enzymatic assays for hydratase vs. dehydrogenase, siRNA knockdown proliferation assays\",\n      \"pmids\": [\"28868548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which C-terminal binding allosterically inhibits the central hydratase domain is unknown\", \"In vivo pharmacokinetics and selectivity not assessed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Isoform-specific analysis resolved a long-standing question about HSD17B4's androgen role: only isoform 2 catalyzes inactivation of testosterone and DHT, and its selective suppression in castration-resistant prostate cancer shifts the androgen metabolic balance toward active 17β-OH forms driving AR signaling.\",\n      \"evidence\": \"Splice form cloning with isoform-specific enzymatic assays, patient tumor RNA analysis, genetic silencing with LC-MS androgen metabolite quantification, AR activity readouts\",\n      \"pmids\": [\"29346776\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of isoform 2 splicing regulation during CRPC progression not identified\", \"Whether restoring isoform 2 can reverse CRPC in vivo is untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Replication of the K669 acetylation–CMA degradation axis in prostate cancer cells confirmed it as a general regulatory mechanism across hormone-responsive tissues, and demonstrated that HSD17B4 protein levels directly modulate cancer cell proliferation, migration, and invasion.\",\n      \"evidence\": \"Co-IP, K669 mutagenesis, CMA assays, siRNA knockdown and overexpression phenotyping, IHC in prostate cancer tissues\",\n      \"pmids\": [\"32678070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of HSD17B4's β-oxidation vs. steroid-metabolizing activities to cancer cell phenotypes not deconvolved\", \"In vivo tumor model validation absent\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for domain-selective catalysis (especially how C-terminal SCP-2 binding by small molecules inhibits the central hydratase domain), the mechanism coupling isoform 2 splicing to CRPC progression, and the tissue-specific determinants that distinguish lethal neonatal from adult-onset HSD17B4 deficiency remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length human HSD17B4 crystal structure capturing interdomain communication\", \"Isoform 2 splicing regulators unidentified\", \"Tissue-specific thresholds of residual activity needed to prevent organ-specific pathology unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 2, 4, 9]},\n      {\"term_id\": \"GO:0016853\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005777\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2, 4, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [3, 9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"CREBBP\",\n      \"SIRT3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}