{"gene":"FDXR","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":1988,"finding":"Human adrenodoxin reductase (FDXR) is encoded by a single gene on chromosome 17cen–q25 and produces two alternatively spliced mRNAs differing by 18 bases (6 codons) near the middle of the coding sequence. The protein is a mitochondrial flavoprotein that initiates electron transport from NADPH to mitochondrial cytochromes P450.","method":"cDNA cloning, Southern blotting of somatic cell hybrids, Northern blotting, RNase protection assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — original molecular cloning with direct sequencing and alternative splicing characterization, replicated by subsequent chromosomal mapping studies","pmids":["2845396"],"is_preprint":false},{"year":1990,"finding":"The human FDXR gene spans ~12 kb and contains 12 exons; the first exon encodes the signal peptide and the second encodes the FAD-binding site, while exon 6 encodes the NADPH-binding site. Two mRNA forms arise by alternative splicing at the 5' end of exon 7, adjacent to the NADPH-binding site. The promoter lacks TATA/CAAT boxes but contains six GGGCGGG (Sp1) motifs, consistent with a housekeeping gene.","method":"Genomic cloning, restriction mapping, DNA sequencing, RNase protection assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — full gene structure determined by direct sequencing with functional domain annotation","pmids":["2236061"],"is_preprint":false},{"year":1991,"finding":"The FDXR gene (adrenodoxin reductase) was mapped to chromosome 17q24–q25 by in situ hybridization, and the ferredoxin (adrenodoxin) gene was mapped to 11q22, establishing that none of the steroidogenic enzyme genes are closely linked to one another.","method":"In situ hybridization on human chromosomes","journal":"DNA and cell biology","confidence":"High","confidence_rationale":"Tier 1 — direct cytogenetic mapping experiment","pmids":["1863359"],"is_preprint":false},{"year":1991,"finding":"Site-directed mutagenesis of human ferredoxin (FDX, the direct electron-transfer partner of FDXR) identified Asp-76 and Asp-79 as residues critical for binding to both FDXR (ferredoxin reductase) and cytochrome P450scc, while other acidic residues (Asp-72, Glu-73) caused differential effects on FDXR vs. P450scc binding, indicating that the two binding interfaces overlap but are not identical. This supports a shuttle model in which ferredoxin alternately docks with FDXR and P450scc.","method":"Site-directed mutagenesis, in vitro binding assays, cholesterol side-chain cleavage reconstitution assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstituted enzymatic assay combined with mutagenesis identifying specific binding determinants","pmids":["1917982"],"is_preprint":false},{"year":2000,"finding":"Crystal structure of the adrenodoxin reductase (AR/FDXR ortholog)–adrenodoxin complex at 2.3 Å resolution revealed the protein–protein interaction interface: key contacts involve Asp-79, Asp-76, Asp-72, and Asp-39 of adrenodoxin with Arg-211, Arg-240, Arg-244, and Lys-27 of the reductase. The [2Fe-2S] cluster of adrenodoxin and the isoalloxazine ring of FAD in the reductase are ~10 Å apart, defining the likely electron-transfer route. Complex formation induces a slight domain rearrangement in the reductase.","method":"X-ray crystallography (2.3 Å resolution crystal structure of the complex)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — high-resolution crystal structure of the functional complex with electron-transfer distance measured","pmids":["11053423"],"is_preprint":false},{"year":2002,"finding":"FDXR (ferredoxin reductase) was identified as a transcriptional target of the p53 family (p53, p63, p73). FDXR is induced by DNA damage in a p53-dependent manner; a p53 response element in the FDXR promoter is directly bound by p53, p63α/γ, and p73α/β in vivo. p53 binding increases histone H3 and H4 acetylation at the FDXR promoter. Overexpression of FDXR sensitizes lung (H1299) and colorectal (HCT116) carcinoma cells to apoptosis induced by 5-fluorouracil, doxorubicin, and H₂O₂, suggesting a feed-forward loop in which cellular stress activates p53→FDXR→ROS-mediated apoptosis.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, tetracycline-inducible overexpression, cell viability/apoptosis assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 — direct ChIP demonstrating p53-family binding to FDXR promoter combined with functional overexpression rescue experiments in multiple cell lines","pmids":["12370809"],"is_preprint":false},{"year":2003,"finding":"FDXR (adrenodoxin reductase) protein and mRNA are expressed in human epidermis, hair follicles, sebaceous ducts, and sebaceous glands, demonstrating that human skin is a steroidogenic tissue that expresses the complete P450scc electron-transport system (FDXR–adrenodoxin–P450scc).","method":"Immunohistochemistry, Western blotting, quantitative RT-PCR, gene array","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal detection methods confirming protein localization, but primarily expression/localization without functional manipulation","pmids":["12787114"],"is_preprint":false},{"year":2011,"finding":"siRNA knockdown of FDXR (the sole human ferredoxin reductase) in multiple human cell lines disrupted iron-sulfur (Fe-S) cluster assembly, caused mitochondrial iron overload, and produced cytosolic iron depletion, demonstrating that FDXR is required for maintaining normal mitochondrial and cellular iron homeostasis as well as Fe-S cluster biogenesis.","method":"siRNA knockdown, activity assays for Fe-S cluster enzymes (aconitase, succinate dehydrogenase), mitochondrial iron quantification, Western blotting","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function in multiple cell lines with specific biochemical readouts (enzyme activities, iron measurements)","pmids":["22101253"],"is_preprint":false},{"year":2017,"finding":"Biallelic loss-of-function mutations in FDXR cause auditory neuropathy and optic atrophy in humans. Mutant FDXR fibroblasts show deregulated iron homeostasis and indirect evidence of mitochondrial iron overload. Functional complementation of the yeast ARH1 (FDXR ortholog) deletion strain by human wild-type FDXR cDNA (but not pathogenic mutants) confirmed pathogenicity. FDXR is identified as the sole human ferredoxin reductase involved in iron-sulfur cluster (ISC) biosynthesis and heme formation.","method":"Whole-exome sequencing, fibroblast iron homeostasis assays, yeast complementation of ARH1 deletion strain","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic mapping combined with functional yeast complementation and patient fibroblast studies across four independent families","pmids":["28965846"],"is_preprint":false},{"year":2017,"finding":"The co-chaperone HSC20 directly binds LYRM7 (an assembly factor for the Rieske Fe-S protein UQCRFS1 of Complex III), and the HSC20–HSPA9–holo-ISCU scaffold complex interacts with the pre-assembled UQCRFS1–LYRM7 intermediate to deliver the Fe-S cluster. This pathway is downstream of the FDXR–FDX electron-transfer system that reduces the ISCU scaffold. Five Fe-S cluster subunits of Complex I also acquire clusters through HSC20, demonstrating a central role for this cochaperone-scaffold in respiratory chain assembly.","method":"Co-immunoprecipitation, affinity purification–mass spectrometry, siRNA knockdown, enzymatic activity assays","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP and MS combined with functional Fe-S cluster activity assays establishing mechanistic pathway","pmids":["28380382"],"is_preprint":false},{"year":2018,"finding":"Biallelic FDXR mutations cause mitochondriopathy with peripheral neuropathy and optic atrophy associated with neuroinflammation. Fdxr mutant mouse brain tissues show increased astrocytes (gliosis) and elevated markers of neurodegeneration, indicating that FDXR deficiency causes central nervous system pathology through an inflammatory mechanism.","method":"Patient clinical evaluation, mouse model histopathology, immunohistochemistry for neurodegeneration and gliosis markers, brain autopsy","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — mouse model with defined pathological phenotype linked to FDXR loss, but mechanistic pathway not fully dissected","pmids":["30250212"],"is_preprint":false},{"year":2019,"finding":"Fhit protein (tumor suppressor) forms a complex with FDXR in the mitochondria, identified by protein cross-linking followed by proteomics. The Fhit–FDXR interaction occurs at electron transport chain complex III, where FDXR transfers electrons from NADPH to cytochrome P450 via ferredoxin. Overexpression of Fhit in Fhit-deficient cancer cells modulates intracellular reactive oxygen species (ROS), increasing ROS and apoptosis under oxidative stress; Fhit-negative cells escape ROS-induced apoptosis. HSP60/10 chaperonin pair is implicated in Fhit mitochondrial import.","method":"Protein cross-linking, proteomics (mass spectrometry), co-immunoprecipitation, ROS measurement, apoptosis assays, in vitro and in vivo cancer cell models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — cross-linking proteomics identifying Fhit–FDXR complex combined with functional ROS and apoptosis readouts, single laboratory","pmids":["30770797"],"is_preprint":false},{"year":2020,"finding":"Loss of FDXR, via its electron-carrier FDX2, increases expression of iron-regulatory protein 2 (IRP2), which subsequently destabilizes TP73 mRNA by binding to an iron response element (IRE) in the TP73 3'UTR, thereby repressing p73 protein expression. Conversely, FDXR is transcriptionally regulated by p73, creating a feedback axis. Compound Trp73+/−;Fdxr+/− mice showed increased cellular senescence but fewer tumors than single heterozygotes, suggesting antagonistic genetic interaction.","method":"Genetically modified mouse models, MEF senescence assays, qRT-PCR, Western blotting, IRE deletion/mutation constructs, RNA stability assays","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including IRE mutagenesis, genetic epistasis in compound mouse models, and mechanistic RNA stability assays","pmids":["32304229"],"is_preprint":false},{"year":2020,"finding":"FDXR mutation causes significant optic transport defects, mitochondrial iron overload, and depolarization of the mitochondrial membrane in a mouse model, further supporting the hypothesis that FDXR's critical role in iron homeostasis underlies neurodegeneration and optic atrophy. Neurodegenerative cell loss in the CNS was also demonstrated.","method":"Fdxr hypomorphic mouse model, optic transport assays, mitochondrial membrane potential measurements, mitochondrial iron quantification, histological analysis","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 2 — in vivo mouse model with multiple functional readouts establishing mechanistic link between FDXR loss and mitochondrial iron/membrane dysfunction","pmids":["32499495"],"is_preprint":false},{"year":2020,"finding":"At least 14 FDXR transcript variants are expressed in human blood, all upregulated after ionizing radiation (IR) in a dose-dependent manner. FDXR-201 and FDXR-208 are the most highly IR-responsive; FDXR-218 and FDXR-219 have no detectable basal expression but are induced by IR. In vitro inflammation transiently counteracted the IR transcriptional response early after exposure. Upregulation was confirmed in vivo in radiotherapy patients.","method":"Quantitative RT-PCR with variant-specific primers, nanopore full-length sequencing, in vivo radiotherapy patient blood samples","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — comprehensive variant characterization by two orthogonal sequencing methods with in vivo validation, but functional roles of individual splice variants not yet determined","pmids":["33113898"],"is_preprint":false},{"year":2023,"finding":"FDXR promotes mitochondrial fatty acid oxidation (FAO) by supporting CPT1A expression in ER+ breast cancer cells. Depletion of FDXR suppressed CPT1A expression and reduced FAO-mediated oxygen consumption. Endocrine treatment increased both FDXR and CPT1A levels. The FDXR–CPT1A–FAO axis was required for growth of both primary and endocrine-resistant breast cancer cells, and combining endocrine therapy with the FAO inhibitor etomoxir synergistically inhibited cell growth.","method":"LC-MS/MS metabolite profiling, RNA microarray, Seahorse XF24 FAO assay, siRNA knockdown, MTS/colony formation assays, 2D and anchorage-independent growth assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 — metabolomics combined with functional FAO assay and loss-of-function studies, single laboratory","pmids":["37207154"],"is_preprint":false}],"current_model":"FDXR (ferredoxin reductase) is a mitochondrial FAD-containing flavoprotein encoded by a single gene on chromosome 17q24–q25 that transfers electrons from NADPH to ferredoxins (FDX1/FDX2), which in turn deliver electrons to mitochondrial cytochromes P450 for steroidogenesis and heme synthesis; FDXR is also the initiating enzyme for iron-sulfur (Fe-S) cluster biogenesis (loss causes mitochondrial iron overload and cytosolic iron depletion), is transcriptionally induced by the p53/p63/p73 family in response to DNA damage to sensitize cells to ROS-mediated apoptosis, regulates p73 tumor suppressor expression via an IRP2-IRE axis downstream of FDX2, interacts with Fhit in the mitochondria to modulate ROS and apoptosis, and supports fatty acid oxidation via CPT1A in breast cancer cells, with biallelic loss-of-function mutations causing a human mitochondriopathy characterized by auditory neuropathy, optic atrophy, and neuroinflammation."},"narrative":{"teleology":[{"year":1988,"claim":"Molecular cloning established FDXR as a single-copy gene encoding a mitochondrial flavoprotein that initiates NADPH-dependent electron transfer to mitochondrial cytochromes P450, resolving the identity of the human adrenodoxin reductase.","evidence":"cDNA cloning, Southern blotting of somatic cell hybrids, and Northern blotting in human tissues","pmids":["2845396"],"confidence":"High","gaps":["Catalytic mechanism and cofactor geometry not determined","Alternative splice-form functional significance unknown","Tissue-specific regulation uncharacterized"]},{"year":1991,"claim":"Mutagenesis of the electron-transfer partner ferredoxin identified specific acidic residues (Asp-76, Asp-79) required for FDXR binding, demonstrating that FDXR and P450scc share overlapping but distinct docking surfaces on ferredoxin, consistent with a shuttle model of sequential electron donation.","evidence":"Site-directed mutagenesis with reconstituted cholesterol side-chain cleavage assay","pmids":["1917982"],"confidence":"High","gaps":["No structural visualization of the complex","Electron-transfer rate constants not measured"]},{"year":2000,"claim":"The crystal structure of the FDXR–adrenodoxin complex at 2.3 Å revealed the electrostatic protein–protein interface and placed the [2Fe–2S] cluster ~10 Å from the FAD isoalloxazine ring, defining the electron-transfer pathway at atomic resolution.","evidence":"X-ray crystallography of the bovine adrenodoxin reductase–adrenodoxin complex","pmids":["11053423"],"confidence":"High","gaps":["Human FDXR structure not solved","Dynamics of domain rearrangement upon complex formation not resolved","Interaction with FDX2 (ISC pathway ferredoxin) not structurally characterized"]},{"year":2002,"claim":"Discovery that FDXR is a direct transcriptional target of p53, p63, and p73 connected the mitochondrial electron-transfer enzyme to the DNA damage response, revealing a feed-forward loop in which stress-activated p53-family members induce FDXR to amplify ROS-mediated apoptosis.","evidence":"Chromatin immunoprecipitation, luciferase reporters, and inducible FDXR overexpression with apoptosis assays in H1299 and HCT116 cells","pmids":["12370809"],"confidence":"High","gaps":["Endogenous ROS source (electron leak site) not pinpointed","Whether p53-induced FDXR apoptosis requires ferredoxin partners not tested"]},{"year":2011,"claim":"Knockdown experiments established that FDXR is essential for Fe–S cluster biogenesis and cellular iron homeostasis, extending its function beyond steroidogenesis to a fundamental role in mitochondrial iron metabolism.","evidence":"siRNA knockdown in multiple human cell lines with aconitase/SDH activity assays and mitochondrial iron quantification","pmids":["22101253"],"confidence":"High","gaps":["Whether FDXR acts exclusively through FDX2 for ISC pathway not distinguished from FDX1 contributions","Mechanism linking FDXR loss to mitochondrial iron import not identified"]},{"year":2017,"claim":"Identification of biallelic FDXR mutations in families with auditory neuropathy and optic atrophy established FDXR deficiency as a human Mendelian mitochondriopathy, confirmed by yeast complementation showing pathogenic variants fail to rescue the ARH1 deletion.","evidence":"Whole-exome sequencing across four families, yeast ARH1 complementation, fibroblast iron homeostasis assays","pmids":["28965846"],"confidence":"High","gaps":["Genotype–phenotype correlation across different mutation types incomplete","Neuronal-specific vulnerability not mechanistically explained"]},{"year":2018,"claim":"A mouse model extended the human disease phenotype by demonstrating that FDXR deficiency drives neuroinflammation with gliosis in the CNS, suggesting that neurodegeneration involves an inflammatory component beyond simple metabolic failure.","evidence":"Fdxr mutant mouse brain histopathology and immunohistochemistry for gliosis and neurodegeneration markers","pmids":["30250212"],"confidence":"Medium","gaps":["Causal versus secondary role of neuroinflammation not dissected","Specific inflammatory signaling pathways not identified"]},{"year":2020,"claim":"Mechanistic dissection revealed that FDXR, via FDX2, controls IRP2 levels which in turn destabilize TP73 mRNA through an IRE in the 3′-UTR, completing a bidirectional feedback loop between the p73 tumor suppressor and FDXR, and compound Fdxr/Trp73 heterozygous mice showed antagonistic genetic interaction on senescence and tumorigenesis.","evidence":"IRE mutagenesis, RNA stability assays, and compound Fdxr+/−;Trp73+/− mouse genetic epistasis","pmids":["32304229"],"confidence":"High","gaps":["IRP2-IRE axis for p73 not validated in human cancer cohorts","Whether p53 is similarly regulated by this axis not tested"]},{"year":2020,"claim":"Fdxr-deficient mice exhibited mitochondrial membrane depolarization and optic axonal transport defects alongside mitochondrial iron overload, linking the iron-homeostasis defect mechanistically to mitochondrial dysfunction and neurodegeneration in vivo.","evidence":"Fdxr hypomorphic mouse model with mitochondrial membrane potential, iron quantification, and optic transport assays","pmids":["32499495"],"confidence":"High","gaps":["Whether iron chelation rescues optic transport not tested","Relative contribution of Fe–S loss versus iron overload to membrane depolarization unknown"]},{"year":2023,"claim":"FDXR was found to promote mitochondrial fatty acid oxidation by supporting CPT1A expression in ER+ breast cancer, identifying a metabolic vulnerability wherein combined endocrine therapy and FAO inhibition synergistically suppressed tumor growth.","evidence":"siRNA knockdown, Seahorse FAO assay, and LC-MS metabolomics in ER+ breast cancer cell lines","pmids":["37207154"],"confidence":"Medium","gaps":["Mechanism by which FDXR controls CPT1A expression not identified","Not replicated in independent cohorts or in vivo models","Whether this FAO role is cancer-specific or generalizable unknown"]},{"year":null,"claim":"Key open questions include the structural basis of human FDXR's differential engagement with FDX1 versus FDX2, the mechanism by which FDXR loss drives mitochondrial iron import and neuroinflammatory signaling, and whether therapeutic iron chelation or FAO modulation can rescue FDXR-deficient phenotypes.","evidence":"","pmids":[],"confidence":"Low","gaps":["Human FDXR crystal structure unavailable","FDX1 vs FDX2 selectivity determinants unresolved","Therapeutic interventions for FDXR-linked mitochondriopathy untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,1,4,7]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,4,9]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,7,8,11,13]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,7,9,15]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[8,10,13]}],"complexes":[],"partners":["FDX1","FDX2","FHIT","TP53","TP73","IRP2","CPT1A"],"other_free_text":[]},"mechanistic_narrative":"FDXR is a mitochondrial FAD-containing NADPH:ferredoxin oxidoreductase that transfers electrons from NADPH to ferredoxins (FDX1/FDX2), supplying reducing equivalents for mitochondrial cytochrome P450-mediated steroidogenesis, heme biosynthesis, and iron–sulfur (Fe–S) cluster assembly [PMID:2845396, PMID:11053423, PMID:22101253]. FDXR is transcriptionally induced by p53-family members (p53, p63, p73) upon DNA damage via a p53-response element in its promoter, sensitizing cells to ROS-dependent apoptosis, and reciprocally regulates p73 expression through an IRP2–IRE-mediated mRNA stability mechanism [PMID:12370809, PMID:32304229]. Loss of FDXR causes mitochondrial iron overload, cytosolic iron depletion, impaired Fe–S enzyme activities, and mitochondrial membrane depolarization, which collectively underlie a progressive neurodegeneration [PMID:22101253, PMID:32499495]. Biallelic loss-of-function FDXR mutations cause a human mitochondriopathy characterized by auditory neuropathy, optic atrophy, and neuroinflammation [PMID:28965846, PMID:30250212]."},"prefetch_data":{"uniprot":{"accession":"P22570","full_name":"NADPH:adrenodoxin oxidoreductase, mitochondrial","aliases":["Ferredoxin--NADP(+) reductase","Ferredoxin reductase"],"length_aa":491,"mass_kda":53.8,"function":"Serves as the first electron transfer protein in all the mitochondrial P450 systems including cholesterol side chain cleavage in all steroidogenic tissues, steroid 11-beta hydroxylation in the adrenal cortex, 25-OH-vitamin D3-24 hydroxylation in the kidney, and sterol C-27 hydroxylation in the liver (By similarity). Also acts as a ferredoxin--NADP(+) reductase essential for coenzyme Q biosynthesis: together with FDX2, transfers the electrons required for the hydroxylation reaction performed by COQ6 (PubMed:38425362)","subcellular_location":"Mitochondrion; Mitochondrion inner membrane","url":"https://www.uniprot.org/uniprotkb/P22570/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/FDXR","classification":"Common Essential","n_dependent_lines":818,"n_total_lines":1208,"dependency_fraction":0.6771523178807947},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FDXR","total_profiled":1310},"omim":[{"mim_id":"620887","title":"MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 9B; MMDS9B","url":"https://www.omim.org/entry/620887"},{"mim_id":"617717","title":"AUDITORY NEUROPATHY AND OPTIC ATROPHY; ANOA","url":"https://www.omim.org/entry/617717"},{"mim_id":"614585","title":"FERREDOXIN 2; FDX2","url":"https://www.omim.org/entry/614585"},{"mim_id":"611729","title":"KINESIN LIGHT CHAIN 2; KLC2","url":"https://www.omim.org/entry/611729"},{"mim_id":"605711","title":"MULTIPLE MITOCHONDRIAL DYSFUNCTIONS SYNDROME 1; MMDS1","url":"https://www.omim.org/entry/605711"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Mitochondria","reliability":"Enhanced"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adrenal gland","ntpm":339.7}],"url":"https://www.proteinatlas.org/search/FDXR"},"hgnc":{"alias_symbol":["ADR","AR"],"prev_symbol":["ADXR"]},"alphafold":{"accession":"P22570","domains":[{"cath_id":"3.40.50.720","chopping":"39-135_363-488","consensus_level":"high","plddt":97.1517,"start":39,"end":488},{"cath_id":"3.50.50.60","chopping":"140-360","consensus_level":"high","plddt":96.1533,"start":140,"end":360}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P22570","model_url":"https://alphafold.ebi.ac.uk/files/AF-P22570-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P22570-F1-predicted_aligned_error_v6.png","plddt_mean":92.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FDXR","jax_strain_url":"https://www.jax.org/strain/search?query=FDXR"},"sequence":{"accession":"P22570","fasta_url":"https://rest.uniprot.org/uniprotkb/P22570.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P22570/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P22570"}},"corpus_meta":[{"pmid":"11943742","id":"PMC_11943742","title":"Androgen receptor (AR) coregulators: an overview.","date":"2002","source":"Endocrine reviews","url":"https://pubmed.ncbi.nlm.nih.gov/11943742","citation_count":706,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26537258","id":"PMC_26537258","title":"Plasma AR and abiraterone-resistant prostate cancer.","date":"2015","source":"Science translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26537258","citation_count":385,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18301781","id":"PMC_18301781","title":"AR, the cell cycle, and prostate cancer.","date":"2008","source":"Nuclear receptor signaling","url":"https://pubmed.ncbi.nlm.nih.gov/18301781","citation_count":270,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"23873027","id":"PMC_23873027","title":"Androgen receptor (AR) differential roles in hormone-related tumors including prostate, bladder, kidney, lung, breast and liver.","date":"2013","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23873027","citation_count":180,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18612376","id":"PMC_18612376","title":"Diverse roles of androgen receptor (AR) domains in AR-mediated signaling.","date":"2008","source":"Nuclear receptor signaling","url":"https://pubmed.ncbi.nlm.nih.gov/18612376","citation_count":176,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31804827","id":"PMC_31804827","title":"Discovery of Highly Potent and Efficient PROTAC Degraders of Androgen Receptor (AR) by Employing Weak Binding Affinity VHL E3 Ligase Ligands.","date":"2019","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31804827","citation_count":162,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28420128","id":"PMC_28420128","title":"AR Signaling and the PI3K Pathway in Prostate Cancer.","date":"2017","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/28420128","citation_count":140,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22245783","id":"PMC_22245783","title":"Androgen receptor (AR) aberrations in castration-resistant prostate cancer.","date":"2012","source":"Molecular and cellular endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/22245783","citation_count":135,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31822498","id":"PMC_31822498","title":"TBCRC 032 IB/II Multicenter Study: Molecular Insights to AR Antagonist and PI3K Inhibitor Efficacy in Patients with AR+ Metastatic Triple-Negative Breast Cancer.","date":"2019","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/31822498","citation_count":128,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27565181","id":"PMC_27565181","title":"Cooperative Dynamics of AR and ER Activity in Breast Cancer.","date":"2016","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/27565181","citation_count":116,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32256939","id":"PMC_32256939","title":"International expert consensus on the management of allergic rhinitis (AR) aggravated by air pollutants: Impact of air pollution on patients with AR: Current knowledge and future strategies.","date":"2020","source":"The World Allergy Organization journal","url":"https://pubmed.ncbi.nlm.nih.gov/32256939","citation_count":114,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30190514","id":"PMC_30190514","title":"Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30190514","citation_count":114,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11773441","id":"PMC_11773441","title":"AR and ER interaction with a p21-activated kinase (PAK6).","date":"2002","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/11773441","citation_count":114,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"20980437","id":"PMC_20980437","title":"CDK9 regulates AR promoter selectivity and cell growth through serine 81 phosphorylation.","date":"2010","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/20980437","citation_count":114,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11875111","id":"PMC_11875111","title":"Inhibition of androgen receptor (AR) function by the reproductive orphan nuclear receptor DAX-1.","date":"2002","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/11875111","citation_count":113,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30995798","id":"PMC_30995798","title":"Everything You Always Wanted to Know about β3-AR * (* But Were Afraid to Ask).","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/30995798","citation_count":112,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33093660","id":"PMC_33093660","title":"Binding pathway determines norepinephrine selectivity for the human β1AR over β2AR.","date":"2020","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/33093660","citation_count":107,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34118355","id":"PMC_34118355","title":"Androgen receptor (AR) heterogeneity in prostate cancer and therapy resistance.","date":"2021","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/34118355","citation_count":104,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21435362","id":"PMC_21435362","title":"Reversal of doxorubicin-resistance by multifunctional nanoparticles in MCF-7/ADR cells.","date":"2011","source":"Journal of controlled release : official journal of the Controlled Release Society","url":"https://pubmed.ncbi.nlm.nih.gov/21435362","citation_count":103,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37038004","id":"PMC_37038004","title":"Landscape of prostate-specific membrane antigen heterogeneity and regulation in AR-positive and AR-negative metastatic prostate cancer.","date":"2023","source":"Nature cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37038004","citation_count":96,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28245550","id":"PMC_28245550","title":"AR Signaling in Breast Cancer.","date":"2017","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/28245550","citation_count":93,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33750801","id":"PMC_33750801","title":"A noncanonical AR addiction drives enzalutamide resistance in prostate cancer.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/33750801","citation_count":82,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33277366","id":"PMC_33277366","title":"KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer.","date":"2020","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33277366","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25798840","id":"PMC_25798840","title":"β2-AR signaling controls trastuzumab resistance-dependent pathway.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/25798840","citation_count":76,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28965846","id":"PMC_28965846","title":"FDXR Mutations Cause Sensorial Neuropathies and Expand the Spectrum of Mitochondrial Fe-S-Synthesis Diseases.","date":"2017","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28965846","citation_count":67,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32868434","id":"PMC_32868434","title":"Analysis of β2AR-Gs and β2AR-Gi complex formation by NMR spectroscopy.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32868434","citation_count":66,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25754347","id":"PMC_25754347","title":"ERG/AKR1C3/AR Constitutes a Feed-Forward Loop for AR Signaling in Prostate Cancer Cells.","date":"2015","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/25754347","citation_count":64,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26769913","id":"PMC_26769913","title":"Androgen receptor (AR) in cardiovascular diseases.","date":"2016","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/26769913","citation_count":62,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26939703","id":"PMC_26939703","title":"Targeting Androgen Receptor (AR)→IL12A Signal Enhances Efficacy of Sorafenib plus NK Cells Immunotherapy to Better Suppress HCC Progression.","date":"2016","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/26939703","citation_count":52,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26728473","id":"PMC_26728473","title":"Moving Beyond the Androgen Receptor (AR): Targeting AR-Interacting Proteins to Treat Prostate Cancer.","date":"2016","source":"Hormones & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26728473","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27583472","id":"PMC_27583472","title":"Identification of an AR Mutation-Negative Class of Androgen Insensitivity by Determining Endogenous AR Activity.","date":"2016","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/27583472","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27991916","id":"PMC_27991916","title":"The HIF/PHF8/AR axis promotes prostate cancer progression.","date":"2016","source":"Oncogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/27991916","citation_count":50,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34071114","id":"PMC_34071114","title":"AR Splicing Variants and Resistance to AR Targeting Agents.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34071114","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36169095","id":"PMC_36169095","title":"Positive epigenetic regulation loop between AR and NSUN2 promotes prostate cancer progression.","date":"2022","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36169095","citation_count":48,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30565725","id":"PMC_30565725","title":"Molecules targeting the androgen receptor (AR) signaling axis beyond the AR-Ligand binding domain.","date":"2018","source":"Medicinal research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/30565725","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27449259","id":"PMC_27449259","title":"A Whole Blood Assay for AR-V7 and ARv567es in Patients with Prostate Cancer.","date":"2016","source":"The Journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/27449259","citation_count":47,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30770797","id":"PMC_30770797","title":"Fhit-Fdxr interaction in the mitochondria: modulation of reactive oxygen species generation and apoptosis in cancer cells.","date":"2019","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/30770797","citation_count":46,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"22286197","id":"PMC_22286197","title":"Methylation of AR locus does not always reflect X chromosome inactivation state.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22286197","citation_count":44,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11818501","id":"PMC_11818501","title":"Domain interactions between coregulator ARA(70) and the androgen receptor (AR).","date":"2002","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/11818501","citation_count":43,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24053777","id":"PMC_24053777","title":"The transcriptional programme of the androgen receptor (AR) in prostate cancer.","date":"2014","source":"BJU international","url":"https://pubmed.ncbi.nlm.nih.gov/24053777","citation_count":42,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11384871","id":"PMC_11384871","title":"The androgen receptor (AR) in syndromes of androgen insensitivity and in prostate cancer.","date":"2001","source":"The Journal of steroid biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11384871","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34545063","id":"PMC_34545063","title":"LncRNA PCBP1-AS1-mediated AR/AR-V7 deubiquitination enhances prostate cancer enzalutamide resistance.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34545063","citation_count":41,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"18805895","id":"PMC_18805895","title":"Role of CYP epoxygenases in A2A AR-mediated relaxation using A2A AR-null and wild-type mice.","date":"2008","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/18805895","citation_count":40,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36370857","id":"PMC_36370857","title":"METTL3 boosts glycolysis and cardiac fibroblast proliferation by increasing AR methylation.","date":"2022","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36370857","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17178871","id":"PMC_17178871","title":"Calmodulin-androgen receptor (AR) interaction: calcium-dependent, calpain-mediated breakdown of AR in LNCaP prostate cancer cells.","date":"2006","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/17178871","citation_count":39,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30827323","id":"PMC_30827323","title":"[EGFR-TKI ADR Management Chinese Expert Consensus].","date":"2019","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30827323","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34939643","id":"PMC_34939643","title":"Regulation of AR mRNA translation in response to acute AR pathway inhibition.","date":"2022","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34939643","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26304926","id":"PMC_26304926","title":"Androgen receptor (AR) suppresses miRNA-145 to promote renal cell carcinoma (RCC) progression independent of VHL status.","date":"2015","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26304926","citation_count":37,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27669432","id":"PMC_27669432","title":"Cell cycle-coupled expansion of AR activity promotes cancer progression.","date":"2016","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/27669432","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26231735","id":"PMC_26231735","title":"Infiltrating neutrophils promote renal cell carcinoma (RCC) proliferation via modulating androgen receptor (AR) → c-Myc signals.","date":"2015","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/26231735","citation_count":36,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"15254774","id":"PMC_15254774","title":"Induction of apoptosis by ar-turmerone on various cell lines.","date":"2004","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15254774","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28901514","id":"PMC_28901514","title":"Multimodal actions of the phytochemical sulforaphane suppress both AR and AR-V7 in 22Rv1 cells: Advocating a potent pharmaceutical combination against castration-resistant prostate cancer.","date":"2017","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/28901514","citation_count":35,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24243687","id":"PMC_24243687","title":"TBLR1 as an androgen receptor (AR) coactivator selectively activates AR target genes to inhibit prostate cancer growth.","date":"2014","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24243687","citation_count":34,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32304229","id":"PMC_32304229","title":"FDXR regulates TP73 tumor suppressor via IRP2 to modulate aging and tumor suppression.","date":"2020","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32304229","citation_count":33,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32499495","id":"PMC_32499495","title":"Integrated analysis of the molecular pathogenesis of FDXR-associated disease.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32499495","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30250212","id":"PMC_30250212","title":"Biallelic mutations in FDXR cause neurodegeneration associated with inflammation.","date":"2018","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30250212","citation_count":32,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38169509","id":"PMC_38169509","title":"ALDH1A1 drives prostate cancer metastases and radioresistance by interplay with AR- and RAR-dependent transcription.","date":"2024","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/38169509","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32885168","id":"PMC_32885168","title":"ACK1-AR and AR-HOXB13 signaling axes: epigenetic regulation of lethal prostate cancers.","date":"2020","source":"NAR cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32885168","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29934310","id":"PMC_29934310","title":"Membrane-associated androgen receptor (AR) potentiates its transcriptional activities by activating heat shock protein 27 (HSP27).","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29934310","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34795264","id":"PMC_34795264","title":"G3BP1 inhibits Cul3SPOP to amplify AR signaling and promote prostate cancer.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34795264","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26263059","id":"PMC_26263059","title":"Rutaecarpine and evodiamine selected as β1-AR inhibitor candidates using β1-AR/CMC-offline-UPLC/MS prevent cardiac ischemia-reperfusion injury via energy modulation.","date":"2015","source":"Journal of pharmaceutical and biomedical analysis","url":"https://pubmed.ncbi.nlm.nih.gov/26263059","citation_count":31,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24265091","id":"PMC_24265091","title":"Cholesterol-β1 AR interaction versus cholesterol-β2 AR interaction.","date":"2013","source":"Proteins","url":"https://pubmed.ncbi.nlm.nih.gov/24265091","citation_count":29,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33113898","id":"PMC_33113898","title":"In Vivo Validation of Alternative FDXR Transcripts in Human Blood in Response to Ionizing Radiation.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33113898","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28536143","id":"PMC_28536143","title":"Aurora Kinase A Promotes AR Degradation via the E3 Ligase CHIP.","date":"2017","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/28536143","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26743901","id":"PMC_26743901","title":"Salubrinal-Mediated Upregulation of eIF2α Phosphorylation Increases Doxorubicin Sensitivity in MCF-7/ADR Cells.","date":"2016","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/26743901","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25124466","id":"PMC_25124466","title":"Association study of ERβ, AR, and CYP19A1 genes and MtF transsexualism.","date":"2014","source":"The journal of sexual medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25124466","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29051161","id":"PMC_29051161","title":"Prostate Cancer Cells Express More Androgen Receptor (AR) Following Androgen Deprivation, Improving Recognition by AR-Specific T Cells.","date":"2017","source":"Cancer immunology research","url":"https://pubmed.ncbi.nlm.nih.gov/29051161","citation_count":27,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33083800","id":"PMC_33083800","title":"Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2.","date":"2020","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/33083800","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33926033","id":"PMC_33926033","title":"Chemical Degradation of Androgen Receptor (AR) Using Bicalutamide Analog-Thalidomide PROTACs.","date":"2021","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33926033","citation_count":26,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34759344","id":"PMC_34759344","title":"Targeting KDM4A-AS1 represses AR/AR-Vs deubiquitination and enhances enzalutamide response in CRPC.","date":"2021","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/34759344","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25158280","id":"PMC_25158280","title":"MEIS1 functions as a potential AR negative regulator.","date":"2014","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/25158280","citation_count":24,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31359506","id":"PMC_31359506","title":"Revisiting the relationships of 2D:4D with androgen receptor (AR) gene and current testosterone levels: Replication study and meta-analyses.","date":"2019","source":"Journal of neuroscience research","url":"https://pubmed.ncbi.nlm.nih.gov/31359506","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33921329","id":"PMC_33921329","title":"Undesirable Status of Prostate Cancer Cells after Intensive Inhibition of AR Signaling: Post-AR Era of CRPC Treatment.","date":"2021","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/33921329","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33069193","id":"PMC_33069193","title":"Natural Compounds as Source of Aldose Reductase (AR) Inhibitors for the Treatment of Diabetic Complications: A Mini Review.","date":"2020","source":"Current drug metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/33069193","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30692044","id":"PMC_30692044","title":"Preclinical study using androgen receptor (AR) degradation enhancer to increase radiotherapy efficacy via targeting radiation-increased AR to better suppress prostate cancer progression.","date":"2019","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/30692044","citation_count":23,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"17166536","id":"PMC_17166536","title":"Hic-5/ARA55: a prostate stroma-specific AR coactivator.","date":"2006","source":"Steroids","url":"https://pubmed.ncbi.nlm.nih.gov/17166536","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30992298","id":"PMC_30992298","title":"Comparative Analysis of AR Variant AR-V567es mRNA Detection Systems Reveals Eminent Variability and Questions the Role as a Clinical Biomarker in Prostate Cancer.","date":"2019","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/30992298","citation_count":21,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35233061","id":"PMC_35233061","title":"OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR.","date":"2022","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/35233061","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33708629","id":"PMC_33708629","title":"Huaier Extract Inhibits Prostate Cancer Growth via Targeting AR/AR-V7 Pathway.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33708629","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"25014244","id":"PMC_25014244","title":"SUMO-specific protease 1 modulates cadmium-augmented transcriptional activity of androgen receptor (AR) by reversing AR SUMOylation.","date":"2014","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/25014244","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30497065","id":"PMC_30497065","title":"Targeting P-Glycoprotein: Nelfinavir Reverses Adriamycin Resistance in K562/ADR Cells.","date":"2018","source":"Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30497065","citation_count":20,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29346310","id":"PMC_29346310","title":"AR Signaling in Human Malignancies: Prostate Cancer and Beyond.","date":"2018","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/29346310","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"24130878","id":"PMC_24130878","title":"Direct interaction between AR and PAK6 in androgen-stimulated PAK6 activation.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24130878","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"9754626","id":"PMC_9754626","title":"Variants in the alpha2A AR adrenergic receptor gene in psychiatric patients.","date":"1998","source":"American journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9754626","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31616657","id":"PMC_31616657","title":"Non-nuclear AR Signaling in Prostate Cancer.","date":"2019","source":"Frontiers in chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31616657","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29707137","id":"PMC_29707137","title":"CNPY2 inhibits MYLIP-mediated AR protein degradation in prostate cancer cells.","date":"2018","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/29707137","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31693867","id":"PMC_31693867","title":"DUSP22 suppresses prostate cancer proliferation by targeting the EGFR-AR axis.","date":"2019","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/31693867","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"29181434","id":"PMC_29181434","title":"Androgen receptor (AR) cistrome in prostate differentiation and cancer progression.","date":"2017","source":"American journal of clinical and experimental urology","url":"https://pubmed.ncbi.nlm.nih.gov/29181434","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"27743893","id":"PMC_27743893","title":"Lgr4 promotes prostate tumorigenesis through the Jmjd2a/AR signaling pathway.","date":"2016","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/27743893","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31234917","id":"PMC_31234917","title":"ASC-J9® increases the bladder cancer chemotherapy efficacy via altering the androgen receptor (AR) and NF-κB survival signals.","date":"2019","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/31234917","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28803809","id":"PMC_28803809","title":"Improved androgen specificity of AR-EcoScreen by CRISPR based glucocorticoid receptor knockout.","date":"2017","source":"Toxicology in vitro : an international journal published in association with BIBRA","url":"https://pubmed.ncbi.nlm.nih.gov/28803809","citation_count":17,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"32742925","id":"PMC_32742925","title":"Coordinated AR and microRNA regulation in prostate cancer.","date":"2020","source":"Asian journal of urology","url":"https://pubmed.ncbi.nlm.nih.gov/32742925","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33753989","id":"PMC_33753989","title":"Androgen receptor (AR) decreases HCC cells migration and invasion via miR-325/ACP5 signaling.","date":"2021","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/33753989","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36408179","id":"PMC_36408179","title":"Increased AR expression in castration-resistant prostate cancer rapidly induces AR signaling reprogramming with the collaboration of EZH2.","date":"2022","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36408179","citation_count":16,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"37207154","id":"PMC_37207154","title":"FDXR drives primary and endocrine-resistant tumor cell growth in ER+ breast cancer via CPT1A-mediated fatty acid oxidation.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37207154","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38531438","id":"PMC_38531438","title":"Capsaicin induces ATP-dependent thermogenesis via the activation of TRPV1/β3-AR/α1-AR in 3T3-L1 adipocytes and mouse model.","date":"2024","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/38531438","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30552993","id":"PMC_30552993","title":"Paris saponin VII reverses chemoresistance in breast MCF-7/ADR cells.","date":"2018","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30552993","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"28287091","id":"PMC_28287091","title":"ELF5-Mediated AR Activation Regulates Prostate Cancer Progression.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28287091","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33709547","id":"PMC_33709547","title":"Androgen receptor (AR) antagonism triggers acute succinate-mediated adaptive responses to reactivate AR signaling.","date":"2021","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33709547","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31723170","id":"PMC_31723170","title":"Ligand induced dissociation of the AR homodimer precedes AR monomer translocation to the nucleus.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31723170","citation_count":13,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26186194","id":"PMC_26186194","title":"The BioPlex Network: A Systematic Exploration of the Human Interactome.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26186194","citation_count":1118,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28514442","id":"PMC_28514442","title":"Architecture of the human interactome defines protein communities and disease networks.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28514442","citation_count":1085,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"33961781","id":"PMC_33961781","title":"Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.","date":"2021","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/33961781","citation_count":705,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8125298","id":"PMC_8125298","title":"Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides.","date":"1994","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8125298","citation_count":492,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15489334","id":"PMC_15489334","title":"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).","date":"2004","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/15489334","citation_count":438,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26638075","id":"PMC_26638075","title":"A Dynamic Protein Interaction Landscape of the Human Centrosome-Cilium Interface.","date":"2015","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/26638075","citation_count":433,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16344560","id":"PMC_16344560","title":"Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes.","date":"2005","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/16344560","citation_count":409,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34079125","id":"PMC_34079125","title":"A proximity-dependent biotinylation map of a human cell.","date":"2021","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/34079125","citation_count":339,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34800366","id":"PMC_34800366","title":"Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.","date":"2021","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/34800366","citation_count":239,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12787114","id":"PMC_12787114","title":"Human skin is a steroidogenic tissue: steroidogenic enzymes and cofactors are expressed in epidermis, normal sebocytes, and an immortalized sebocyte cell line (SEB-1).","date":"2003","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/12787114","citation_count":224,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"12370809","id":"PMC_12370809","title":"The ferredoxin reductase gene is regulated by the p53 family and sensitizes cells to oxidative stress-induced apoptosis.","date":"2002","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12370809","citation_count":178,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"22101253","id":"PMC_22101253","title":"Both human ferredoxins 1 and 2 and ferredoxin reductase are important for iron-sulfur cluster biogenesis.","date":"2011","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/22101253","citation_count":160,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1917982","id":"PMC_1917982","title":"Site-specific mutations in human ferredoxin that affect binding to ferredoxin reductase and cytochrome P450scc.","date":"1991","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/1917982","citation_count":146,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11053423","id":"PMC_11053423","title":"Adrenodoxin reductase-adrenodoxin complex structure suggests electron transfer path in steroid biosynthesis.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11053423","citation_count":143,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"1863359","id":"PMC_1863359","title":"Regional mapping of genes encoding human steroidogenic enzymes: P450scc to 15q23-q24, adrenodoxin to 11q22; adrenodoxin reductase to 17q24-q25; and P450c17 to 10q24-q25.","date":"1991","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1863359","citation_count":122,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27465491","id":"PMC_27465491","title":"Role of SUMO activating enzyme in cancer stem cell maintenance and self-renewal.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27465491","citation_count":95,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2845396","id":"PMC_2845396","title":"Human adrenodoxin reductase: two mRNAs encoded by a single gene on chromosome 17cen----q25 are expressed in steroidogenic tissues.","date":"1988","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2845396","citation_count":90,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28380382","id":"PMC_28380382","title":"A Single Adaptable Cochaperone-Scaffold Complex Delivers Nascent Iron-Sulfur Clusters to Mammalian Respiratory Chain Complexes I-III.","date":"2017","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/28380382","citation_count":78,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31586073","id":"PMC_31586073","title":"The midbody interactome reveals unexpected roles for PP1 phosphatases in cytokinesis.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31586073","citation_count":74,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35256949","id":"PMC_35256949","title":"Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy.","date":"2021","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/35256949","citation_count":66,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35831314","id":"PMC_35831314","title":"Scalable multiplex co-fractionation/mass spectrometry platform for accelerated protein interactome discovery.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/35831314","citation_count":65,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"28700943","id":"PMC_28700943","title":"A Role for Mitochondrial Translation in Promotion of Viability in K-Ras Mutant Cells.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28700943","citation_count":64,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"36424410","id":"PMC_36424410","title":"MYC multimers shield stalled replication forks from RNA polymerase.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/36424410","citation_count":63,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2236061","id":"PMC_2236061","title":"Cloning and sequence of the human adrenodoxin reductase gene.","date":"1990","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2236061","citation_count":56,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"2969697","id":"PMC_2969697","title":"Molecular cloning and sequence analysis of human placental ferredoxin.","date":"1988","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/2969697","citation_count":53,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30559450","id":"PMC_30559450","title":"The deubiquitylating enzyme UCHL3 regulates Ku80 retention at sites of DNA damage.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30559450","citation_count":46,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47359,"output_tokens":1900,"usd":0.085289},"stage2":{"model":"claude-opus-4-6","input_tokens":5155,"output_tokens":2056,"usd":0.115763},"total_usd":0.492819,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":60241,"output_tokens":5246,"usd":0.129707},"round2_rules_fired":"R2,R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":8258,"output_tokens":2670,"usd":0.16206}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"Biallelic mutations in FDXR cause auditory neuropathy and optic atrophy; FDXR encodes the sole human mitochondrial ferredoxin reductase required for iron-sulfur cluster (ISC) biosynthesis and heme formation, and FDXR mutant fibroblasts show deregulated iron homeostasis and indirect evidence of mitochondrial iron overload. Functional complementation in yeast ARH1-deleted strain confirmed pathogenicity of these mutations.\",\n      \"method\": \"Whole-exome sequencing of patients, fibroblast functional assays, yeast complementation assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient-derived cell functional assays plus orthologous yeast complementation; multiple families replicated\",\n      \"pmids\": [\"28965846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FDXR regulates the tumor suppressor p73 (TP73) via the iron-binding protein IRP2: loss of FDXR, acting through FDX2, increases IRP2 expression, which then binds an iron response element in the 3'UTR of TP73 mRNA to destabilize it, thereby reducing p73 protein levels. This FDXR-p73 axis contributes to aging and tumor suppression.\",\n      \"method\": \"Genetically modified mouse models (Fdxr+/- and Trp73+/- single and compound knockouts), MEF senescence assays, 3'UTR reporter assays, western blot, qPCR in multiple human cancer cell lines\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (mouse genetics, 3'UTR reporter, multiple cell lines), clear mechanistic pathway established\",\n      \"pmids\": [\"32304229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FDXR mutations lead to mitochondrial iron overload, depolarization of the mitochondrial membrane, optic axonal transport defects, and neurodegeneration in the CNS, consistent with FDXR's critical role in iron homeostasis and electron transport chain function.\",\n      \"method\": \"Fdxr hypomorphic mouse model, optic transport assays, mitochondrial membrane potential measurements, molecular analysis of iron markers, comparison with patient autopsy material\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model plus multiple functional readouts, validated against human pathology\",\n      \"pmids\": [\"32499495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Biallelic FDXR mutations cause mitochondriopathy, peripheral neuropathy, and optic atrophy associated with neuroinflammation; Fdxr mutant mouse brain shows increased astrocytes, markers of neurodegeneration and gliosis, indicating inflammation as a major pathological mechanism.\",\n      \"method\": \"Patient case reports, Fdxr mutant mouse brain histopathology, immunostaining for neurodegeneration and gliosis markers, comparison with patient brain autopsy\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mouse model with histopathological readouts, single lab but multiple methods\",\n      \"pmids\": [\"30250212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FDXR physically interacts with Fhit protein in mitochondria (within a complex containing HSP60/10 chaperonins), and this interaction modulates reactive oxygen species (ROS) production; Fhit overexpression in Fhit-deficient cancer cells increases ROS following peroxide treatment and promotes apoptosis under oxidative stress, an effect mediated through FDXR's role in electron transport chain complex III.\",\n      \"method\": \"Protein cross-linking, proteomics/mass spectrometry, co-immunoprecipitation, ROS measurement, apoptosis assays in lung cancer cells\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal proteomics and Co-IP identifying the complex, functional ROS/apoptosis readouts; single lab\",\n      \"pmids\": [\"30770797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Multiple FDXR transcript variants (at least 14 identified) are upregulated in a dose-dependent manner following ionizing radiation (IR) exposure in human blood; specific variants (FDXR-201 and FDXR-208) show the highest IR responsiveness by nanopore sequencing; variants FDXR-218 and FDXR-219 show no basal expression but are induced by IR, establishing FDXR transcriptional responsiveness to DNA damage as a functional property of the locus.\",\n      \"method\": \"qPCR with variant-specific primers, in vitro IR dose-response, in vivo blood sampling from radiotherapy patients, full-length nanopore sequencing\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo validation of IR-induced transcription, multiple splice variants characterized; single lab\",\n      \"pmids\": [\"33113898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FDXR promotes fatty acid oxidation (FAO) in ER+ breast cancer cells by supporting CPT1A expression; depletion of FDXR suppresses CPT1A expression and reduces FAO-mediated oxygen consumption, inhibiting primary and endocrine-resistant breast cancer cell growth. Endocrine treatment increases both FDXR and CPT1A expression, revealing a FDXR-CPT1A-FAO signaling axis.\",\n      \"method\": \"LC-MS/MS metabolite profiling, RNA microarray, Seahorse XF24 FAO assay, siRNA knockdown, MTS/colony formation assays in primary and endocrine-resistant breast cancer cells\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (metabolomics, Seahorse, functional growth assays) in single lab establishing mechanistic axis\",\n      \"pmids\": [\"37207154\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FDXR (ferredoxin reductase) is a mitochondrial flavoprotein that transfers electrons from NADPH to cytochrome P450s via ferredoxin 1/2, functioning as the sole human ferredoxin reductase required for iron-sulfur cluster biosynthesis, heme synthesis, and steroidogenesis; loss of FDXR causes mitochondrial iron overload, impaired electron transport chain function, and elevated ROS, leading to neurodegeneration, and FDXR also regulates the tumor suppressor p73 through an IRP2-mediated mRNA stability mechanism, supports fatty acid oxidation via CPT1A, interacts with Fhit in the mitochondria to modulate ROS-induced apoptosis, and its transcription is strongly induced by ionizing radiation through a p53-dependent pathway.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEEP papers.\n\n**Classification:**\n- Papers [1]-[24] in the retrieved corpus (except [25], [37], [54], [55], [56], [63], [95]) are about Androgen Receptor (AR gene/NR3C4), adrenergic receptors (β1-AR, β2-AR, A2A AR), aldose reductase, or ar-turmerone — all EXCLUDE (alias collision).\n- Paper [25] FDXR mutations → KEEP\n- Paper [37] Fhit-Fdxr interaction → KEEP\n- Paper [54] FDXR regulates TP73 → KEEP\n- Paper [55] Integrated analysis FDXR-associated disease → KEEP\n- Paper [56] Biallelic FDXR mutations → KEEP\n- Paper [63] FDXR transcripts in blood/radiation → KEEP\n- Paper [95] FDXR drives breast cancer via CPT1A → KEEP\n\n**Gene2pubmed curated papers:**\n- [15] Ferredoxin reductase gene regulated by p53 → KEEP (FDXR)\n- [16] FDX1, FDX2, FDXR in iron-sulfur cluster biogenesis → KEEP\n- [17] Site-specific mutations in human ferredoxin affecting FDXR binding → KEEP (directly about FDXR function)\n- [18] Adrenodoxin reductase-adrenodoxin complex structure → KEEP (FDXR ortholog/direct protein)\n- [19] Regional mapping of adrenodoxin reductase gene → KEEP (chromosomal mapping of FDXR)\n- [21] Human adrenodoxin reductase mRNAs → KEEP (FDXR)\n- [28] Cloning human adrenodoxin reductase gene → KEEP (FDXR)\n- [14] Steroidogenic enzymes in skin including adrenodoxin reductase → KEEP (FDXR expression/function)\n- [1],[2],[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13] — cDNA/interactome datasets; mention FDXR incidentally in large-scale data → these are not mechanistic FDXR papers; EXCLUDE for discovery extraction\n- [20] SUMO activating enzyme → EXCLUDE (not FDXR)\n- [22] HSC20 scaffold for Fe-S clusters → KEEP (directly about FDXR pathway/Fe-S biogenesis with mechanistic detail)\n- [23] Midbody interactome → EXCLUDE\n- [24] HDAC inhibitors/Parkin → EXCLUDE\n- [25] CF/MS → EXCLUDE\n- [26] K-Ras mitochondrial translation → EXCLUDE\n- [27] MYC multimers → EXCLUDE\n- [29] Human placental ferredoxin cloning → KEEP (directly about FDX/FDXR electron transfer partner)\n- [30] UCHL3 → EXCLUDE\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1988,\n      \"finding\": \"Human adrenodoxin reductase (FDXR) is encoded by a single gene on chromosome 17cen–q25 and produces two alternatively spliced mRNAs differing by 18 bases (6 codons) near the middle of the coding sequence. The protein is a mitochondrial flavoprotein that initiates electron transport from NADPH to mitochondrial cytochromes P450.\",\n      \"method\": \"cDNA cloning, Southern blotting of somatic cell hybrids, Northern blotting, RNase protection assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original molecular cloning with direct sequencing and alternative splicing characterization, replicated by subsequent chromosomal mapping studies\",\n      \"pmids\": [\"2845396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"The human FDXR gene spans ~12 kb and contains 12 exons; the first exon encodes the signal peptide and the second encodes the FAD-binding site, while exon 6 encodes the NADPH-binding site. Two mRNA forms arise by alternative splicing at the 5' end of exon 7, adjacent to the NADPH-binding site. The promoter lacks TATA/CAAT boxes but contains six GGGCGGG (Sp1) motifs, consistent with a housekeeping gene.\",\n      \"method\": \"Genomic cloning, restriction mapping, DNA sequencing, RNase protection assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — full gene structure determined by direct sequencing with functional domain annotation\",\n      \"pmids\": [\"2236061\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The FDXR gene (adrenodoxin reductase) was mapped to chromosome 17q24–q25 by in situ hybridization, and the ferredoxin (adrenodoxin) gene was mapped to 11q22, establishing that none of the steroidogenic enzyme genes are closely linked to one another.\",\n      \"method\": \"In situ hybridization on human chromosomes\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct cytogenetic mapping experiment\",\n      \"pmids\": [\"1863359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Site-directed mutagenesis of human ferredoxin (FDX, the direct electron-transfer partner of FDXR) identified Asp-76 and Asp-79 as residues critical for binding to both FDXR (ferredoxin reductase) and cytochrome P450scc, while other acidic residues (Asp-72, Glu-73) caused differential effects on FDXR vs. P450scc binding, indicating that the two binding interfaces overlap but are not identical. This supports a shuttle model in which ferredoxin alternately docks with FDXR and P450scc.\",\n      \"method\": \"Site-directed mutagenesis, in vitro binding assays, cholesterol side-chain cleavage reconstitution assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstituted enzymatic assay combined with mutagenesis identifying specific binding determinants\",\n      \"pmids\": [\"1917982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Crystal structure of the adrenodoxin reductase (AR/FDXR ortholog)–adrenodoxin complex at 2.3 Å resolution revealed the protein–protein interaction interface: key contacts involve Asp-79, Asp-76, Asp-72, and Asp-39 of adrenodoxin with Arg-211, Arg-240, Arg-244, and Lys-27 of the reductase. The [2Fe-2S] cluster of adrenodoxin and the isoalloxazine ring of FAD in the reductase are ~10 Å apart, defining the likely electron-transfer route. Complex formation induces a slight domain rearrangement in the reductase.\",\n      \"method\": \"X-ray crystallography (2.3 Å resolution crystal structure of the complex)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution crystal structure of the functional complex with electron-transfer distance measured\",\n      \"pmids\": [\"11053423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"FDXR (ferredoxin reductase) was identified as a transcriptional target of the p53 family (p53, p63, p73). FDXR is induced by DNA damage in a p53-dependent manner; a p53 response element in the FDXR promoter is directly bound by p53, p63α/γ, and p73α/β in vivo. p53 binding increases histone H3 and H4 acetylation at the FDXR promoter. Overexpression of FDXR sensitizes lung (H1299) and colorectal (HCT116) carcinoma cells to apoptosis induced by 5-fluorouracil, doxorubicin, and H₂O₂, suggesting a feed-forward loop in which cellular stress activates p53→FDXR→ROS-mediated apoptosis.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, tetracycline-inducible overexpression, cell viability/apoptosis assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct ChIP demonstrating p53-family binding to FDXR promoter combined with functional overexpression rescue experiments in multiple cell lines\",\n      \"pmids\": [\"12370809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"FDXR (adrenodoxin reductase) protein and mRNA are expressed in human epidermis, hair follicles, sebaceous ducts, and sebaceous glands, demonstrating that human skin is a steroidogenic tissue that expresses the complete P450scc electron-transport system (FDXR–adrenodoxin–P450scc).\",\n      \"method\": \"Immunohistochemistry, Western blotting, quantitative RT-PCR, gene array\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal detection methods confirming protein localization, but primarily expression/localization without functional manipulation\",\n      \"pmids\": [\"12787114\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"siRNA knockdown of FDXR (the sole human ferredoxin reductase) in multiple human cell lines disrupted iron-sulfur (Fe-S) cluster assembly, caused mitochondrial iron overload, and produced cytosolic iron depletion, demonstrating that FDXR is required for maintaining normal mitochondrial and cellular iron homeostasis as well as Fe-S cluster biogenesis.\",\n      \"method\": \"siRNA knockdown, activity assays for Fe-S cluster enzymes (aconitase, succinate dehydrogenase), mitochondrial iron quantification, Western blotting\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in multiple cell lines with specific biochemical readouts (enzyme activities, iron measurements)\",\n      \"pmids\": [\"22101253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Biallelic loss-of-function mutations in FDXR cause auditory neuropathy and optic atrophy in humans. Mutant FDXR fibroblasts show deregulated iron homeostasis and indirect evidence of mitochondrial iron overload. Functional complementation of the yeast ARH1 (FDXR ortholog) deletion strain by human wild-type FDXR cDNA (but not pathogenic mutants) confirmed pathogenicity. FDXR is identified as the sole human ferredoxin reductase involved in iron-sulfur cluster (ISC) biosynthesis and heme formation.\",\n      \"method\": \"Whole-exome sequencing, fibroblast iron homeostasis assays, yeast complementation of ARH1 deletion strain\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic mapping combined with functional yeast complementation and patient fibroblast studies across four independent families\",\n      \"pmids\": [\"28965846\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The co-chaperone HSC20 directly binds LYRM7 (an assembly factor for the Rieske Fe-S protein UQCRFS1 of Complex III), and the HSC20–HSPA9–holo-ISCU scaffold complex interacts with the pre-assembled UQCRFS1–LYRM7 intermediate to deliver the Fe-S cluster. This pathway is downstream of the FDXR–FDX electron-transfer system that reduces the ISCU scaffold. Five Fe-S cluster subunits of Complex I also acquire clusters through HSC20, demonstrating a central role for this cochaperone-scaffold in respiratory chain assembly.\",\n      \"method\": \"Co-immunoprecipitation, affinity purification–mass spectrometry, siRNA knockdown, enzymatic activity assays\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP and MS combined with functional Fe-S cluster activity assays establishing mechanistic pathway\",\n      \"pmids\": [\"28380382\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Biallelic FDXR mutations cause mitochondriopathy with peripheral neuropathy and optic atrophy associated with neuroinflammation. Fdxr mutant mouse brain tissues show increased astrocytes (gliosis) and elevated markers of neurodegeneration, indicating that FDXR deficiency causes central nervous system pathology through an inflammatory mechanism.\",\n      \"method\": \"Patient clinical evaluation, mouse model histopathology, immunohistochemistry for neurodegeneration and gliosis markers, brain autopsy\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mouse model with defined pathological phenotype linked to FDXR loss, but mechanistic pathway not fully dissected\",\n      \"pmids\": [\"30250212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Fhit protein (tumor suppressor) forms a complex with FDXR in the mitochondria, identified by protein cross-linking followed by proteomics. The Fhit–FDXR interaction occurs at electron transport chain complex III, where FDXR transfers electrons from NADPH to cytochrome P450 via ferredoxin. Overexpression of Fhit in Fhit-deficient cancer cells modulates intracellular reactive oxygen species (ROS), increasing ROS and apoptosis under oxidative stress; Fhit-negative cells escape ROS-induced apoptosis. HSP60/10 chaperonin pair is implicated in Fhit mitochondrial import.\",\n      \"method\": \"Protein cross-linking, proteomics (mass spectrometry), co-immunoprecipitation, ROS measurement, apoptosis assays, in vitro and in vivo cancer cell models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cross-linking proteomics identifying Fhit–FDXR complex combined with functional ROS and apoptosis readouts, single laboratory\",\n      \"pmids\": [\"30770797\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Loss of FDXR, via its electron-carrier FDX2, increases expression of iron-regulatory protein 2 (IRP2), which subsequently destabilizes TP73 mRNA by binding to an iron response element (IRE) in the TP73 3'UTR, thereby repressing p73 protein expression. Conversely, FDXR is transcriptionally regulated by p73, creating a feedback axis. Compound Trp73+/−;Fdxr+/− mice showed increased cellular senescence but fewer tumors than single heterozygotes, suggesting antagonistic genetic interaction.\",\n      \"method\": \"Genetically modified mouse models, MEF senescence assays, qRT-PCR, Western blotting, IRE deletion/mutation constructs, RNA stability assays\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including IRE mutagenesis, genetic epistasis in compound mouse models, and mechanistic RNA stability assays\",\n      \"pmids\": [\"32304229\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FDXR mutation causes significant optic transport defects, mitochondrial iron overload, and depolarization of the mitochondrial membrane in a mouse model, further supporting the hypothesis that FDXR's critical role in iron homeostasis underlies neurodegeneration and optic atrophy. Neurodegenerative cell loss in the CNS was also demonstrated.\",\n      \"method\": \"Fdxr hypomorphic mouse model, optic transport assays, mitochondrial membrane potential measurements, mitochondrial iron quantification, histological analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo mouse model with multiple functional readouts establishing mechanistic link between FDXR loss and mitochondrial iron/membrane dysfunction\",\n      \"pmids\": [\"32499495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"At least 14 FDXR transcript variants are expressed in human blood, all upregulated after ionizing radiation (IR) in a dose-dependent manner. FDXR-201 and FDXR-208 are the most highly IR-responsive; FDXR-218 and FDXR-219 have no detectable basal expression but are induced by IR. In vitro inflammation transiently counteracted the IR transcriptional response early after exposure. Upregulation was confirmed in vivo in radiotherapy patients.\",\n      \"method\": \"Quantitative RT-PCR with variant-specific primers, nanopore full-length sequencing, in vivo radiotherapy patient blood samples\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — comprehensive variant characterization by two orthogonal sequencing methods with in vivo validation, but functional roles of individual splice variants not yet determined\",\n      \"pmids\": [\"33113898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FDXR promotes mitochondrial fatty acid oxidation (FAO) by supporting CPT1A expression in ER+ breast cancer cells. Depletion of FDXR suppressed CPT1A expression and reduced FAO-mediated oxygen consumption. Endocrine treatment increased both FDXR and CPT1A levels. The FDXR–CPT1A–FAO axis was required for growth of both primary and endocrine-resistant breast cancer cells, and combining endocrine therapy with the FAO inhibitor etomoxir synergistically inhibited cell growth.\",\n      \"method\": \"LC-MS/MS metabolite profiling, RNA microarray, Seahorse XF24 FAO assay, siRNA knockdown, MTS/colony formation assays, 2D and anchorage-independent growth assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — metabolomics combined with functional FAO assay and loss-of-function studies, single laboratory\",\n      \"pmids\": [\"37207154\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FDXR (ferredoxin reductase) is a mitochondrial FAD-containing flavoprotein encoded by a single gene on chromosome 17q24–q25 that transfers electrons from NADPH to ferredoxins (FDX1/FDX2), which in turn deliver electrons to mitochondrial cytochromes P450 for steroidogenesis and heme synthesis; FDXR is also the initiating enzyme for iron-sulfur (Fe-S) cluster biogenesis (loss causes mitochondrial iron overload and cytosolic iron depletion), is transcriptionally induced by the p53/p63/p73 family in response to DNA damage to sensitize cells to ROS-mediated apoptosis, regulates p73 tumor suppressor expression via an IRP2-IRE axis downstream of FDX2, interacts with Fhit in the mitochondria to modulate ROS and apoptosis, and supports fatty acid oxidation via CPT1A in breast cancer cells, with biallelic loss-of-function mutations causing a human mitochondriopathy characterized by auditory neuropathy, optic atrophy, and neuroinflammation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FDXR is a mitochondrial flavoprotein that serves as the sole human ferredoxin reductase, transferring electrons from NADPH via ferredoxin to support iron-sulfur cluster biosynthesis, heme formation, and electron transport chain function [PMID:28965846, PMID:32499495]. Loss of FDXR causes mitochondrial iron overload, membrane depolarization, elevated ROS, and neurodegeneration with neuroinflammation, and biallelic mutations cause auditory neuropathy and optic atrophy [PMID:28965846, PMID:32499495, PMID:30250212]. Beyond its canonical electron transfer role, FDXR regulates the tumor suppressor p73 through an IRP2-mediated mRNA destabilization mechanism linking iron homeostasis to tumor suppression and aging, supports fatty acid oxidation through CPT1A, and interacts with Fhit in mitochondria to modulate ROS-induced apoptosis [PMID:32304229, PMID:37207154, PMID:30770797]. FDXR transcription is strongly induced by ionizing radiation in a dose-dependent manner, with multiple transcript variants differentially responsive to DNA damage [PMID:33113898].\",\n  \"teleology\": [\n    {\n      \"year\": 2017,\n      \"claim\": \"Establishing that FDXR is the sole human mitochondrial ferredoxin reductase essential for iron-sulfur cluster and heme biosynthesis, and that its loss causes a Mendelian neurodegenerative disorder, answered the question of whether FDXR is non-redundant in human mitochondrial electron transfer and linked it to disease.\",\n      \"evidence\": \"Whole-exome sequencing of multiple families with auditory neuropathy/optic atrophy, fibroblast iron homeostasis assays, yeast ARH1 complementation\",\n      \"pmids\": [\"28965846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Precise structural basis for how individual patient mutations impair FDXR catalytic activity was not determined\",\n        \"Whether iron overload is the primary driver of neurodegeneration or a secondary consequence was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrating neuroinflammation (astrogliosis, gliosis) in Fdxr mutant mouse brain established that inflammation is a major pathological mechanism downstream of FDXR deficiency, beyond simple mitochondrial dysfunction.\",\n      \"evidence\": \"Fdxr mutant mouse brain histopathology, immunostaining for neurodegeneration and gliosis markers, comparison with patient autopsy\",\n      \"pmids\": [\"30250212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study without independent replication in a different mouse model\",\n        \"Whether neuroinflammation is a cause or consequence of neuronal death was not dissected\",\n        \"Molecular signaling pathway from FDXR loss to glial activation was not identified\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identifying a physical interaction between FDXR and Fhit within a mitochondrial HSP60/10-containing complex, and showing this modulates ROS production and apoptosis via complex III, revealed a non-canonical role for FDXR in oxidative-stress-mediated cell death signaling.\",\n      \"evidence\": \"Protein cross-linking, mass spectrometry, co-immunoprecipitation, ROS and apoptosis assays in lung cancer cells\",\n      \"pmids\": [\"30770797\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab finding; reciprocal Co-IP was performed but independent replication is lacking\",\n        \"Whether the FDXR-Fhit interaction is direct or mediated entirely by chaperonins was not resolved\",\n        \"Physiological relevance outside cancer cell lines not tested\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Three advances in 2020 broadened FDXR's functional scope: (1) showing that FDXR loss drives mitochondrial iron overload, membrane depolarization, and optic axonal transport defects in vivo established the pathophysiological cascade; (2) demonstrating that FDXR regulates p73 via an IRP2-iron response element mechanism connected mitochondrial iron metabolism to tumor suppression; and (3) characterizing dose-dependent induction of multiple FDXR transcript variants by ionizing radiation identified FDXR as a DNA damage-responsive locus.\",\n      \"evidence\": \"Fdxr hypomorphic mouse model with optic transport and membrane potential assays [PMID:32499495]; Fdxr+/- and Trp73+/- compound knockout mice, 3'UTR reporter assays, multiple cell lines [PMID:32304229]; qPCR/nanopore sequencing of IR-treated human blood in vitro and in vivo [PMID:33113898]\",\n      \"pmids\": [\"32499495\", \"32304229\", \"33113898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the IRP2-p73 axis operates in non-transformed human tissues in vivo is untested\",\n        \"The p53-dependent transcription factor mechanism driving IR-induced FDXR expression was not directly dissected in these studies\",\n        \"Functional consequences of specific FDXR splice variants remain uncharacterized\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealing that FDXR promotes fatty acid oxidation by supporting CPT1A expression in breast cancer cells established a metabolic axis linking mitochondrial electron transfer to lipid catabolism and endocrine therapy resistance.\",\n      \"evidence\": \"LC-MS/MS metabolomics, Seahorse FAO assays, siRNA knockdown, colony formation in primary and endocrine-resistant ER+ breast cancer cells\",\n      \"pmids\": [\"37207154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study; mechanism by which FDXR controls CPT1A expression (transcriptional vs. post-transcriptional) not determined\",\n        \"Whether the FDXR-CPT1A axis is relevant in non-cancerous tissues or other cancer types is unknown\",\n        \"Whether iron-sulfur cluster supply or another FDXR function mediates the CPT1A effect is unresolved\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include: (1) the structural and catalytic basis for how specific FDXR mutations differentially impair its functions; (2) whether FDXR's roles in p73 regulation, fatty acid oxidation, and ROS-mediated apoptosis are mechanistically interconnected or independent of its canonical ferredoxin reductase activity; and (3) which FDXR splice variants are functionally relevant in specific tissues.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of human FDXR with disease-associated mutations\",\n        \"No reconstituted in vitro system linking FDXR catalytic activity to CPT1A or p73 regulation\",\n        \"Tissue-specific functional requirements of individual FDXR splice variants remain uncharacterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FDX2\", \"IRP2\", \"TP73\", \"FHIT\", \"CPT1A\", \"HSP60\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"FDXR is a mitochondrial FAD-containing NADPH:ferredoxin oxidoreductase that transfers electrons from NADPH to ferredoxins (FDX1/FDX2), supplying reducing equivalents for mitochondrial cytochrome P450-mediated steroidogenesis, heme biosynthesis, and iron–sulfur (Fe–S) cluster assembly [PMID:2845396, PMID:11053423, PMID:22101253]. FDXR is transcriptionally induced by p53-family members (p53, p63, p73) upon DNA damage via a p53-response element in its promoter, sensitizing cells to ROS-dependent apoptosis, and reciprocally regulates p73 expression through an IRP2–IRE-mediated mRNA stability mechanism [PMID:12370809, PMID:32304229]. Loss of FDXR causes mitochondrial iron overload, cytosolic iron depletion, impaired Fe–S enzyme activities, and mitochondrial membrane depolarization, which collectively underlie a progressive neurodegeneration [PMID:22101253, PMID:32499495]. Biallelic loss-of-function FDXR mutations cause a human mitochondriopathy characterized by auditory neuropathy, optic atrophy, and neuroinflammation [PMID:28965846, PMID:30250212].\",\n  \"teleology\": [\n    {\n      \"year\": 1988,\n      \"claim\": \"Molecular cloning established FDXR as a single-copy gene encoding a mitochondrial flavoprotein that initiates NADPH-dependent electron transfer to mitochondrial cytochromes P450, resolving the identity of the human adrenodoxin reductase.\",\n      \"evidence\": \"cDNA cloning, Southern blotting of somatic cell hybrids, and Northern blotting in human tissues\",\n      \"pmids\": [\"2845396\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism and cofactor geometry not determined\", \"Alternative splice-form functional significance unknown\", \"Tissue-specific regulation uncharacterized\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Mutagenesis of the electron-transfer partner ferredoxin identified specific acidic residues (Asp-76, Asp-79) required for FDXR binding, demonstrating that FDXR and P450scc share overlapping but distinct docking surfaces on ferredoxin, consistent with a shuttle model of sequential electron donation.\",\n      \"evidence\": \"Site-directed mutagenesis with reconstituted cholesterol side-chain cleavage assay\",\n      \"pmids\": [\"1917982\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural visualization of the complex\", \"Electron-transfer rate constants not measured\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"The crystal structure of the FDXR–adrenodoxin complex at 2.3 Å revealed the electrostatic protein–protein interface and placed the [2Fe–2S] cluster ~10 Å from the FAD isoalloxazine ring, defining the electron-transfer pathway at atomic resolution.\",\n      \"evidence\": \"X-ray crystallography of the bovine adrenodoxin reductase–adrenodoxin complex\",\n      \"pmids\": [\"11053423\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Human FDXR structure not solved\", \"Dynamics of domain rearrangement upon complex formation not resolved\", \"Interaction with FDX2 (ISC pathway ferredoxin) not structurally characterized\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Discovery that FDXR is a direct transcriptional target of p53, p63, and p73 connected the mitochondrial electron-transfer enzyme to the DNA damage response, revealing a feed-forward loop in which stress-activated p53-family members induce FDXR to amplify ROS-mediated apoptosis.\",\n      \"evidence\": \"Chromatin immunoprecipitation, luciferase reporters, and inducible FDXR overexpression with apoptosis assays in H1299 and HCT116 cells\",\n      \"pmids\": [\"12370809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous ROS source (electron leak site) not pinpointed\", \"Whether p53-induced FDXR apoptosis requires ferredoxin partners not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Knockdown experiments established that FDXR is essential for Fe–S cluster biogenesis and cellular iron homeostasis, extending its function beyond steroidogenesis to a fundamental role in mitochondrial iron metabolism.\",\n      \"evidence\": \"siRNA knockdown in multiple human cell lines with aconitase/SDH activity assays and mitochondrial iron quantification\",\n      \"pmids\": [\"22101253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether FDXR acts exclusively through FDX2 for ISC pathway not distinguished from FDX1 contributions\", \"Mechanism linking FDXR loss to mitochondrial iron import not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identification of biallelic FDXR mutations in families with auditory neuropathy and optic atrophy established FDXR deficiency as a human Mendelian mitochondriopathy, confirmed by yeast complementation showing pathogenic variants fail to rescue the ARH1 deletion.\",\n      \"evidence\": \"Whole-exome sequencing across four families, yeast ARH1 complementation, fibroblast iron homeostasis assays\",\n      \"pmids\": [\"28965846\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype–phenotype correlation across different mutation types incomplete\", \"Neuronal-specific vulnerability not mechanistically explained\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"A mouse model extended the human disease phenotype by demonstrating that FDXR deficiency drives neuroinflammation with gliosis in the CNS, suggesting that neurodegeneration involves an inflammatory component beyond simple metabolic failure.\",\n      \"evidence\": \"Fdxr mutant mouse brain histopathology and immunohistochemistry for gliosis and neurodegeneration markers\",\n      \"pmids\": [\"30250212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal versus secondary role of neuroinflammation not dissected\", \"Specific inflammatory signaling pathways not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Mechanistic dissection revealed that FDXR, via FDX2, controls IRP2 levels which in turn destabilize TP73 mRNA through an IRE in the 3′-UTR, completing a bidirectional feedback loop between the p73 tumor suppressor and FDXR, and compound Fdxr/Trp73 heterozygous mice showed antagonistic genetic interaction on senescence and tumorigenesis.\",\n      \"evidence\": \"IRE mutagenesis, RNA stability assays, and compound Fdxr+/−;Trp73+/− mouse genetic epistasis\",\n      \"pmids\": [\"32304229\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"IRP2-IRE axis for p73 not validated in human cancer cohorts\", \"Whether p53 is similarly regulated by this axis not tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Fdxr-deficient mice exhibited mitochondrial membrane depolarization and optic axonal transport defects alongside mitochondrial iron overload, linking the iron-homeostasis defect mechanistically to mitochondrial dysfunction and neurodegeneration in vivo.\",\n      \"evidence\": \"Fdxr hypomorphic mouse model with mitochondrial membrane potential, iron quantification, and optic transport assays\",\n      \"pmids\": [\"32499495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether iron chelation rescues optic transport not tested\", \"Relative contribution of Fe–S loss versus iron overload to membrane depolarization unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"FDXR was found to promote mitochondrial fatty acid oxidation by supporting CPT1A expression in ER+ breast cancer, identifying a metabolic vulnerability wherein combined endocrine therapy and FAO inhibition synergistically suppressed tumor growth.\",\n      \"evidence\": \"siRNA knockdown, Seahorse FAO assay, and LC-MS metabolomics in ER+ breast cancer cell lines\",\n      \"pmids\": [\"37207154\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which FDXR controls CPT1A expression not identified\", \"Not replicated in independent cohorts or in vivo models\", \"Whether this FAO role is cancer-specific or generalizable unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of human FDXR's differential engagement with FDX1 versus FDX2, the mechanism by which FDXR loss drives mitochondrial iron import and neuroinflammatory signaling, and whether therapeutic iron chelation or FAO modulation can rescue FDXR-deficient phenotypes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Human FDXR crystal structure unavailable\", \"FDX1 vs FDX2 selectivity determinants unresolved\", \"Therapeutic interventions for FDXR-linked mitochondriopathy untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 1, 4, 7]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 4, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 7, 8, 11, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 7, 9, 15]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [8, 10, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"FDX1\",\n      \"FDX2\",\n      \"FHIT\",\n      \"TP53\",\n      \"TP73\",\n      \"IRP2\",\n      \"CPT1A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}