{"gene":"STEAP4","run_date":"2026-06-10T07:46:42","timeline":{"discoveries":[{"year":2013,"finding":"Crystal structure of the Steap4 oxidoreductase domain was determined, revealing a novel interdomain flavin-binding site that shuttles electrons between the oxidoreductase and transmembrane domains. Detailed kinetic analysis showed physiologically relevant Km values for Fe(3+) and Cu(2+), flavin-dependent NADPH oxidase activity greater than Steap3, and retained activity at acidic pH suggesting intracellular organelle function. Structure-function mutagenesis showed disordered N-terminal residues do not contribute to enzymatic activity.","method":"X-ray crystallography, in vitro kinetic assay, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure solved with functional kinetic characterization and mutagenesis in single rigorous study","pmids":["23733181"],"is_preprint":false},{"year":2007,"finding":"STAMP2 (STEAP4) acts as a critical integrator of inflammatory and metabolic responses in adipocytes. STAMP2-knockout mice on a regular diet develop spontaneous insulin resistance, glucose intolerance, mild hyperglycemia, dyslipidemia, and fatty liver disease with overt visceral adipose tissue inflammation, establishing STAMP2 as essential for metabolic homeostasis.","method":"Germline knockout mouse model, metabolic phenotyping, inflammatory marker analysis","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined metabolic and inflammatory phenotypes, highly cited foundational study","pmids":["17482547"],"is_preprint":false},{"year":2012,"finding":"Stamp2 controls macrophage inflammation through NADPH homeostasis: absence of Stamp2 results in significantly elevated cellular NADPH levels, and the exaggerated inflammatory response in Stamp2-/- macrophages is rescued by wild-type but not reductase-deficient Stamp2. Chemical and genetic suppression of NADPH production in Stamp2-/- macrophages reverts the heightened inflammatory response. Bone marrow transplantation confirmed Stamp2 in myeloid cells is sufficient to protect against atherosclerosis.","method":"Knockout macrophages, NADPH measurement, reductase-deficient mutant rescue, bone marrow transplantation, atherosclerosis model","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods including mutant rescue, genetic epistasis via BMT, and metabolite measurement","pmids":["22704678"],"is_preprint":false},{"year":2013,"finding":"Steap4 functions as an endosomal ferrireductase in osteoclasts. Knockdown of Steap4 by lentivirus-mediated shRNA inhibits osteoclast formation in vitro and decreases cellular ferrous iron, reactive oxygen species, and activation of CREB, a transcription factor required for osteoclast differentiation downstream of RANKL-induced calcium signaling.","method":"Lentivirus-mediated shRNA knockdown, ferrous iron measurement, ROS assay, CREB phosphorylation assay, osteoclast differentiation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean loss-of-function with multiple biochemical readouts in a defined cellular differentiation context","pmids":["23990467"],"is_preprint":false},{"year":2020,"finding":"IL-17 induces cellular copper uptake via induction of STEAP4 (a metalloreductase). Elevated intracellular copper activates the E3 ligase XIAP, which potentiates IL-17-induced NF-κB activation and suppresses caspase-3 activity. STEAP4 deficiency abrogated IL-17-induced copper uptake and colon tumor formation in a colitis-associated tumorigenesis model.","method":"Gene knockout mouse model, copper measurement, XIAP activity assay, NF-κB reporter, caspase-3 activity assay, colitis-associated tumorigenesis model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with multiple biochemical pathway readouts and in vivo tumor model","pmids":["32060280"],"is_preprint":false},{"year":2017,"finding":"STEAP4 is a ferrireductase induced by hypoxia in colitis; its expression leads to dysregulation of mitochondrial iron balance and enhanced reactive oxygen species production, increasing susceptibility to colitis and promoting colon tumor formation. Mitochondrial iron chelation therapy improved colitis, establishing mitochondrial iron dysregulation as a key mechanism.","method":"Unbiased proteomics, mouse colitis model, colitis-associated cancer model, mitochondrial iron chelation","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multi-model in vivo approach with pharmacological and genetic validation of mitochondrial iron mechanism","pmids":["29078383"],"is_preprint":false},{"year":2005,"finding":"STAMP2 (STEAP4) localizes primarily to the Golgi complex, trans-Golgi network, plasma membrane, and vesicular-tubular cytosolic structures. It co-localizes with Early Endosome Antigen 1 (EEA1), suggesting involvement in secretory/endocytic pathways. Expression is androgen-regulated in androgen receptor-positive LNCaP cells but not in AR-negative PC-3 or DU145 cells. Ectopic expression increases prostate cancer cell growth and colony formation.","method":"GFP-fusion live-cell imaging, immunofluorescence confocal microscopy, co-localization with EEA1, androgen treatment assays, colony formation assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct localization experiments with functional growth assay, single lab","pmids":["15897894"],"is_preprint":false},{"year":2001,"finding":"TIARP (STEAP4) is a TNF-alpha-inducible transmembrane protein that emerges at the plasma membrane during adipocyte differentiation. Commitment to the differentiation process is required for cytokine responsiveness, and differentiation itself induces sharp TIARP mRNA expression.","method":"Differential display, immunofluorescence, Northern blot, TNF-alpha treatment of 3T3-L1 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct expression and localization experiments, replicated for TNF-alpha regulation, single lab","pmids":["11443137"],"is_preprint":false},{"year":2005,"finding":"TIARP (STEAP4) co-localizes with caveolin-1 as patches at the plasma membrane of 3T3-L1 adipocytes, detected by confocal microscopy. Immunoblot analysis showed TIARP is completely detergent-extractible from membranes, whereas caveolin-1 is present in both extractible and -insoluble pools, indicating TIARP partitions within caveolae signaling domains.","method":"Confocal microscopy co-localization, detergent extraction fractionation, immunoblot","journal":"Biology of the cell","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct co-localization and biochemical fractionation, single lab with two methods","pmids":["15836432"],"is_preprint":false},{"year":2009,"finding":"STEAP4 associates with focal adhesion kinase (FAK) and regulates FAK activity through Y397 phosphorylation. STEAP4 expression inhibits anchorage-independent cell growth. CpG sequences in the STEAP4 promoter are frequently methylated in androgen-independent DU145 prostate cancer cells, and demethylation treatment induces STEAP4 expression.","method":"Co-immunoprecipitation, FAK phosphorylation assay, soft agar colony assay, methylation-specific PCR, demethylation treatment","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP with functional phosphorylation readout, single lab, single method for interaction","pmids":["19787193"],"is_preprint":false},{"year":2010,"finding":"STEAP4 promotes insulin-stimulated glucose uptake in mature human adipocytes. Overexpression of STEAP4 does not affect adipogenesis but enhances 2-deoxy-D-glucose uptake in a PI3K-dependent manner. Expression is regulated by adipokines TNF-alpha, IL-6, and leptin.","method":"2-deoxy-D-[3H]-glucose uptake assay, oil red O staining, Western blotting, RT-PCR","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct functional glucose uptake assay with overexpression, single lab","pmids":["20127040"],"is_preprint":false},{"year":2010,"finding":"Hepatic STEAP4 transcription is a direct target of phosphorylated STAT3 in mouse liver, induced by IL-6. In addition, CCAAT/enhancer-binding protein alpha (C/EBPα) is required for STEAP4 regulation during feeding/fasting and obesity, acting in concert with STAT3; both factors bind the proximal steap4 promoter in vivo.","method":"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, IL-6 treatment, STAT3 phosphorylation analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP in vivo with promoter reporter assays and genetic intervention, multiple orthogonal methods","pmids":["20304921"],"is_preprint":false},{"year":2011,"finding":"siRNA-mediated STEAP4 knockdown significantly decreases insulin-stimulated glucose transport in human adipocytes by reducing GLUT4 translocation to the plasma membrane via attenuated Akt phosphorylation. STEAP4 does not interact with EEA1 (confirmed by FRET analysis) and does not alter EEA1 protein expression, establishing that the effect on glucose uptake is EEA1-independent.","method":"siRNA knockdown, 2-deoxy-glucose uptake assay, GLUT4 translocation assay, Akt phosphorylation western blot, FRET analysis","journal":"Molecular medicine reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with defined molecular pathway readout, two orthogonal methods (functional + FRET), single lab","pmids":["21468601"],"is_preprint":false},{"year":2015,"finding":"STAMP2 increases reactive oxygen species through its iron reductase activity, which also depletes NADPH levels in prostate cancer cells. Knockdown inhibits proliferation, colony formation, anchorage-independent growth, and increases apoptosis. STAMP2 effects are mediated at least in part through ATF4, whose expression is regulated by ROS. Systemic nanoliposomal siRNA silencing of STAMP2 profoundly inhibited PCa tumor growth in two preclinical models.","method":"ROS measurement, NADPH assay, shRNA/siRNA knockdown, in vitro proliferation/apoptosis assays, xenograft models, nanoliposomal siRNA delivery","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods with in vitro and in vivo validation of iron reductase-mediated ROS/NADPH mechanism","pmids":["25680860"],"is_preprint":false},{"year":2015,"finding":"Hepatic STAMP2 physically interacts with and decreases the stability of hepatitis B virus X protein (HBx), counteracting HBx-induced hepatic lipid accumulation and insulin resistance. STAMP2 prevented HBx-induced degradation of IRS1 protein and restored insulin-mediated inhibition of gluconeogenic enzyme expression.","method":"Co-immunoprecipitation, protein stability assay, HBx transgenic mouse analysis, Western blot for IRS1 and gluconeogenic enzymes","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP demonstrating physical interaction with functional protein stability and signaling readouts, single lab","pmids":["23095254"],"is_preprint":false},{"year":2015,"finding":"Hepatic STAMP2 modulates insulin sensitivity via IRS-1 stability. Knockdown of hepatic STAMP2 by siRNA accelerated hepatic steatosis and insulin resistance in HFD mice; adenoviral STAMP2 delivery improved hepatic steatosis and counteracted oleic acid-induced insulin resistance by modulating IRS-1 stability.","method":"In vivo siRNA knockdown, adenoviral overexpression, glucose/insulin tolerance tests, IRS-1 protein stability assay, in vitro NAFLD model","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — bidirectional manipulation (KD + OE) in vivo and in vitro with defined molecular mechanism, single lab","pmids":["25646886"],"is_preprint":false},{"year":2011,"finding":"STEAP4 is induced by TNF-alpha in fibroblast-like synoviocytes (FLS) and localizes to endosomal/lysosomal compartments. STEAP4 downregulation by siRNA enhanced IL-6 mRNA expression; overexpression suppressed IL-6 and IL-8 expression, inhibited cell proliferation, and induced apoptosis via caspase-3 in FLS.","method":"siRNA knockdown, plasmid overexpression, IL-6/IL-8 ELISA, proliferation assay, caspase-3 apoptosis assay, immunofluorescence localization","journal":"Modern rheumatology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — bidirectional manipulation with multiple functional readouts and subcellular localization, single lab","pmids":["21633911"],"is_preprint":false},{"year":2012,"finding":"STEAP4 overexpression in neutrophil-like HL60 cells down-regulates neutrophil migration in a transwell assay. TIARP/STEAP4-deficient neutrophils overexpress CXCR1 and CXCR2 and show enhanced migration activity facilitated by CXCL2 in vitro and in vivo.","method":"GFP-STEAP4 overexpression, transwell migration assay, DNA microarray of TIARP-/- neutrophils, in vivo K/BxN serum transfer arthritis model","journal":"Clinical and experimental rheumatology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct functional migration assay with genetic KO microarray validation, single lab","pmids":["22244520"],"is_preprint":false},{"year":2016,"finding":"TIARP (STEAP4) attenuates arthritis by independently down-regulating CXCL2 and IL-6 production by fibroblast-like synoviocytes and reducing CXCR1/CXCR2 expression in neutrophils, reducing neutrophil migration into arthritic joints. IL-6R blockade significantly attenuated arthritis in TIARP-/- mice with diminished neutrophil recruitment.","method":"TIARP-/- mouse K/BxN serum transfer model, DNA microarray, in vitro neutrophil migration assay, anti-IL-6R antibody blockade, immunohistochemistry","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse model with pharmacological rescue and in vitro mechanistic validation, single lab","pmids":["27995997"],"is_preprint":false},{"year":2019,"finding":"ER stress (induced by thapsigargin or tunicamycin) significantly reduces STAMP2 mRNA and protein expression and alters its intracellular localization in adipocytes, reducing total iron reductase activity. TNF-alpha has the opposite effect. Promoter analysis by reporter assays and ChIP showed that ER stress disrupts C/EBPα-mediated STAMP2 transcription.","method":"ER stress inducers, iron reductase activity assay, luciferase promoter reporter, ChIP assay, immunofluorescence localization","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity measurement plus ChIP and reporter assays linking ER stress to C/EBPα-STAMP2 axis, single lab","pmids":["30710574"],"is_preprint":false},{"year":2012,"finding":"C/EBPβ directly regulates STEAP4 gene transcription by binding the C/EBPβ binding motif at -73/-59 bp of the STEAP4 promoter, as demonstrated by progressive deletions, site-directed mutations of the promoter construct, and ChIP assays. C/EBPβ protein levels increase with LPS treatment in parallel with STEAP4 and its splice variant induction.","method":"Promoter deletion constructs, site-directed mutagenesis, luciferase reporter assay, chromatin immunoprecipitation (ChIP)","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary promoter methods (deletion + mutation + ChIP) in single study, single lab","pmids":["23262293"],"is_preprint":false},{"year":2018,"finding":"Articular chondrocytes gain resistance to lipotoxicity through a PKCK2-STAMP2-FSP27 signaling cascade that promotes lipid droplet accumulation, sequestering free fatty acids. Lipid droplet accumulation confers resistance to oleate-induced lipotoxicity; when FFAs are freed from lipid droplets, lipotoxicity occurs regardless of saturation status.","method":"HFD-induced OA mouse model, in vitro chondrocyte treatment, lipid droplet quantification, PKCK2 inhibition, STAMP2 and FSP27 knockdown/overexpression","journal":"Bone research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro models with genetic manipulation of pathway components, single lab","pmids":["30002945"],"is_preprint":false},{"year":2018,"finding":"AMPK functions upstream of STAMP2 to regulate its expression. Cilostazol activates AMPK in vivo and in vitro, which drives transcriptional upregulation of STAMP2, reversing HFD- and oleic acid-induced STAMP2 downregulation and ameliorating hepatic steatosis.","method":"HFD mouse model, HepG2 cells, AMPK inhibitors/activators, Western blot, qPCR, in vivo and in vitro STAMP2 expression analysis","journal":"Molecular pharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pharmacological and genetic epistasis placing AMPK upstream of STAMP2, replicated in vivo and in vitro, single lab","pmids":["30366981"],"is_preprint":false},{"year":2021,"finding":"STEAP4 is a downstream effector molecule specifically in the IL-17/Th17 signaling pathway in the CNS. STEAP4 knockout mice are resistant to Th17- but not Th1-induced experimental autoimmune encephalomyelitis (EAE); ablation of STEAP4 specifically in CNS-resident cells (Nestin-Cre STEAP4fl/fl) attenuated disease in both active and passive Th17 EAE.","method":"Global and conditional (Nestin-Cre) STEAP4 knockout mice, active immunization EAE, passive Th17/Th1 transfer EAE, microarray analysis","journal":"Journal of neuroinflammation","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with cell-type-specific rescue establishes CNS-resident cell STEAP4 as Th17-specific effector, multiple genetic approaches","pmids":["33879167"],"is_preprint":false},{"year":2022,"finding":"In Stamp2-deficient mice after myocardial ischemia-reperfusion, augmented neutrophil infiltration produces excess ROS activating the redox-sensitive p38 MAPK, driving fibroblast-to-myofibroblast transdifferentiation and cardiac fibrosis. Antibody-mediated neutrophil depletion in Stamp2-/- mice reduced deterioration of cardiac function to WT levels, establishing PMN as the key cellular mediator.","method":"Stamp2-/- mouse I/R model, echocardiography, histology, ROS measurement, p38 MAPK assay, MPO measurement, neutrophil depletion antibody","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with rescue by neutrophil depletion establishing mechanism, single lab","pmids":["34691017"],"is_preprint":false},{"year":2023,"finding":"FOXO1 directly binds to the promoter regions of CD36 and STEAP4 genes and regulates their transcriptional activities, as confirmed by chromatin immunoprecipitation (ChIP) and site-directed mutagenesis of promoter binding sites in bovine adipocytes.","method":"Chromatin immunoprecipitation (ChIP), site-directed mutagenesis, luciferase reporter assay, siRNA knockdown","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP plus promoter mutagenesis validating FOXO1 as direct transcriptional regulator of STEAP4, single lab","pmids":["37506793"],"is_preprint":false},{"year":2023,"finding":"STEAP4 physically interacts with AKT and inhibits the PI3K/AKT pathway, suppressing cisplatin resistance in hepatocellular carcinoma. Double knockdown of STEAP4 and AKT significantly inhibited cisplatin resistance, and STEAP4 expression negatively correlates with PI3K/AKT pathway activity in clinical specimens.","method":"Co-immunoprecipitation, siRNA double knockdown, cell viability/colony/apoptosis assays, xenograft tumor model, clinical specimen correlation","journal":"Cancer & metabolism","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP for interaction plus functional rescue experiment and in vivo validation, single lab","pmids":["38111065"],"is_preprint":false},{"year":2023,"finding":"STEAP4 regulates proliferation and apoptosis of prostate epithelial cells (BPH context) through the AKT/mTOR signaling pathway. STEAP4 knockdown induces apoptosis and inhibits cell survival; AKT/mTOR activator SC79 reverses STEAP4 knockdown-induced apoptosis, and AKT/mTOR inhibitor MK2206 reduces STEAP4 OE-induced viability increase.","method":"siRNA knockdown, overexpression, CCK-8 assay, flow cytometry, SC79/MK2206 pharmacological rescue, Western blot for AKT/mTOR pathway","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pharmacological rescue experiments placing STEAP4 upstream of AKT/mTOR, single lab","pmids":["37866665"],"is_preprint":false},{"year":2020,"finding":"Recombinant FGF21 ameliorates hepatic steatosis and insulin resistance through upregulation of STAMP2 expression, and improves hepatic iron overload (HIO) through hepatic STAMP2-mediated upregulation of ferroportin expression, an iron exporter.","method":"HFD mouse model, human NAFLD samples, HepG2 cells, adenoviral STAMP2 overexpression, ferroportin Western blot, iron measurement","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro models with defined molecular target (ferroportin), single lab","pmids":["32721044"],"is_preprint":false},{"year":2016,"finding":"STAMP2 is required for human adipose-derived stem cell (ASC) differentiation into adipocytes. shRNA-mediated STAMP2 knockdown in ASCs significantly suppresses adipogenesis and impairs optimal expression of adipogenic genes and adipocyte metabolic function. ASC-derived adipocyte-mediated stimulation of prostate tumor growth in nude mice is significantly reduced upon STAMP2 knockdown.","method":"shRNA knockdown in human ASCs, adipogenesis assay, adipogenic gene expression, nude mouse co-implantation tumor model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in human primary cells with in vivo tumor growth readout, single lab","pmids":["29190878"],"is_preprint":false},{"year":2022,"finding":"STAMP2 suppresses autophagy in prostate cancer cells through modulation of the integrated stress response axis (ATF4 pathway). STAMP2 also regulates mitochondrial respiration.","method":"STAMP2 knockdown/overexpression, autophagy flux assay, mitochondrial respiration measurement (Seahorse)","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assays without detailed mechanistic dissection of the pathway, single lab, limited methods described in abstract","pmids":["35141021"],"is_preprint":false},{"year":2025,"finding":"HERP interacts with STEAP4 to prevent its ubiquitin-mediated proteasomal degradation, stabilizing STEAP4 protein. HERP regulates adipogenesis through STEAP4 in a PPARγ-dependent manner. Enhancing STEAP4 expression ameliorated adipose expansion and metabolic disorders in HERP-KO mice.","method":"Co-immunoprecipitation, HERP KO mouse, STEAP4 ubiquitination assay, PPARγ pathway analysis, adenoviral STEAP4 rescue","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP plus functional rescue in KO mice with PPARγ pathway linkage, single lab","pmids":["41249464"],"is_preprint":false},{"year":2025,"finding":"STEAP4 promotes intracellular Fe2+ accumulation and ROS elevation, upregulating C/EBPβ expression. C/EBPβ in turn binds a functional site in the Steap4 promoter and upregulates Steap4, establishing a self-amplifying Steap4/Fe2+-ROS/C/EBPβ positive feedback loop. Knockdown of Steap4 or C/EBPβ suppressed BMSC adipocyte differentiation.","method":"Knockdown studies, C/EBPβ promoter binding assay, Fe2+ measurement, ROS assay, adipogenic differentiation assay, deferoxamine treatment in vivo","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — bidirectional genetic manipulation with promoter interaction and iron/ROS measurements, single lab","pmids":["41201016"],"is_preprint":false},{"year":2026,"finding":"SIRT3 deacetylates STEAP4 at lysine 404, which is required for its mitochondrial targeting. HBx attenuates SIRT3, impairing STEAP4 deacetylation and abolishing its mitochondrial localization. Loss of mitochondrial STEAP4 drives a switch from TCA cycle respiration to glycolysis, reducing cuproptosis sensitivity. Restoring STEAP4 or activating SIRT3 with honokiol re-instates mitochondrial STEAP4 and re-sensitizes HBV-related HCC cells to cuproptosis.","method":"Deacetylation assay, site-specific mutagenesis (K404), mitochondrial fractionation, metabolic flux analysis, HBx-transgenic mice, pharmacological SIRT3 activation, orthotopic HCC model","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — specific acetylation site identified by mutagenesis, mitochondrial targeting linked mechanistically to deacetylation, multiple in vivo and in vitro models","pmids":["41840161"],"is_preprint":false},{"year":2025,"finding":"STEAP4 reduces intracellular ROS by selectively enhancing activities of antioxidant enzymes SOD and GPX, independently of its canonical ferric reductase function. The consequent ROS reduction inhibits NRF2 nuclear translocation, suppressing NOTCH1 transcription through direct NRF2 promoter binding; restoring ROS levels reversed this inhibitory effect in TNBC cells.","method":"ROS measurement, SOD/GPX activity assays, NRF2 nuclear translocation assay, NOTCH1 promoter assay, NRF2 ChIP-like analysis, overexpression/knockdown","journal":"International journal of biological macromolecules","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — enzymatic activity measurements plus nuclear translocation assays and promoter binding establishing ROS/NRF2/NOTCH1 pathway, single lab","pmids":["41276039"],"is_preprint":false},{"year":2025,"finding":"STEAP4 knockout significantly reduces colon tumorigenesis in a genetically engineered mouse model. STEAP4 knockdown attenuates the NRF2-NQO1 signaling pathway in colon cancer cells, inducing apoptosis and autophagy. STEAP4 overexpression amplifies ROS production and activates NRF2-NQO1 in a ferric iron (Fe3+)-dependent manner. NQO1-bioactivatable drugs are highly effective at eradicating STEAP4-overexpressing colon cancer cells.","method":"Genetically engineered KO mouse model, shRNA knockdown, STEAP4 overexpression, ROS assay, NRF2/NQO1 pathway analysis, xenograft growth assay, NQO1-targeted drug treatment","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in vivo with mechanistic dissection of Fe3+-dependent ROS/NRF2-NQO1 axis in vitro and in vivo, multiple orthogonal approaches","pmids":["40205952"],"is_preprint":false},{"year":2025,"finding":"Adipocyte-specific Steap4 deficiency impairs respiratory chain complex activity and causes mitochondrial dysfunction in white adipose tissue. Mass spectrometry identified STEAP4 interactomes as mitochondrial proteins and RNA splicing proteins; Steap4 deficiency altered RNA splicing patterns with enriched mitochondrial functions by RNA-seq. Brown adipocyte-specific Steap4 deficiency impaired mitochondrial function, increased brown fat whitening, reduced energy expenditure, and exacerbated insulin resistance.","method":"Adipocyte-conditional KO, mass spectrometry interactome, RNA-seq splicing analysis, respiratory chain complex activity assay, metabolic cage energy expenditure measurement","journal":"iScience","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with multi-omics (proteomics + RNA-seq) and direct mitochondrial function measurements, multiple orthogonal methods","pmids":["39995871"],"is_preprint":false},{"year":2026,"finding":"STEAP4 maintains lysosomal iron homeostasis and prevents lysosomal membrane damage. In liver-specific STEAP4 KO mice, APAP treatment caused iron buildup in endolysosomes, lysosomal membrane damage, release of cathepsin B, impaired mTOR activity, defective mitophagy, and reduced hepatocyte proliferation at 48h. STEAP4 is not essential during early injury but is critical for liver regeneration.","method":"Liver-specific KO (Alb-Cre Steap4fl/fl), APAP model, lysosomal fractionation, cathepsin B assay, mTOR signaling analysis, iron measurement, DFP chelation rescue","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with pharmacological rescue and defined subcellular (endolysosomal) iron mechanism with multiple functional readouts","pmids":["41838890"],"is_preprint":false},{"year":2025,"finding":"Lithium exposure upregulates FOXO1, which promotes FOXO1-mediated STEAP4 transcription. Upregulated STEAP4 elevates intracellular Cu+ levels causing cuproptosis in trophoblasts, inducing miscarriage. Therapeutic knockdown of FOXO1 or STEAP4, or Cu chelation with TTM, suppressed placental cuproptosis and alleviated miscarriage in Li-exposed mice.","method":"Mouse Li-exposure model, ChIP for FOXO1-STEAP4 promoter, Cu+ measurement, cuproptosis markers, AAV-mediated KD, TTM treatment","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-validated transcriptional axis with pharmacological and genetic rescue, single lab","pmids":["40855689"],"is_preprint":false},{"year":2025,"finding":"REL (a NF-κB subunit) enhances STEAP4 expression by binding to its promoter, as demonstrated by transcriptome analysis and in vitro cellular experiments in valvular interstitial cells. STEAP4-mediated iron overload drives ferroptosis contributing to aortic valve calcification.","method":"Transcriptome analysis, luciferase reporter or promoter binding assay, STEAP4 knockdown/overexpression in hVICs, ferroptosis inhibitor treatment, ApoE-/- HFD and wire-injury mouse models","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — REL-STEAP4 promoter interaction with in vivo and in vitro functional validation, single lab","pmids":["41115643"],"is_preprint":false},{"year":2025,"finding":"HDAC2 directly interacts with SOX2 to inhibit its acetylation and destabilize the SOX2 protein. SOX2 binds to the STAMP2 promoter region and modulates its transcriptional activity. The HDAC2/SOX2/STAMP2 axis regulates macrophage activation in septic lung injury.","method":"Co-immunoprecipitation, luciferase assay, chromatin immunoprecipitation (ChIP), CLP mouse model, LPS-macrophage model","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for HDAC2-SOX2 interaction plus ChIP for SOX2-STAMP2 promoter binding, single lab","pmids":["40877891"],"is_preprint":false},{"year":2026,"finding":"NAMPT regulates STEAP4 expression through the SIRT1-C/EBPβ axis: NAMPT drives NAD+ synthesis enabling SIRT1 deacetylase activity, which deacetylates C/EBPβ to allow its function as a STEAP4 transcriptional activator. STEAP4 in turn upregulates NRF2 expression and nuclear translocation to combat oxidative stress in NAFLD.","method":"NAMPT/SIRT1 inhibition in HFD mice, C/EBPβ acetylation assay, STEAP4 promoter analysis, NRF2 nuclear translocation assay","journal":"Journal of molecular cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple components of signaling axis tested with pharmacological inhibition in vivo and biochemical assays, single lab","pmids":["41324246"],"is_preprint":false},{"year":2025,"finding":"GATA3 transcriptionally activates STEAP4 by binding to its promoter, as confirmed by ChIP-PCR and dual-luciferase assays. STEAP4 knockdown inhibited Th2 differentiation and Th2-related cytokine production in vitro; STEAP4 knockdown rescued the promoting effects of GATA3 overexpression on Th2 differentiation, placing STEAP4 downstream of GATA3 in this pathway.","method":"ChIP-PCR, dual-luciferase reporter assay, siRNA knockdown, GATA3 overexpression, Th2 differentiation assay, OVA mouse model","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirming GATA3-STEAP4 promoter interaction with genetic epistasis (STEAP4 KD rescues GATA3 OE effect), single lab","pmids":["41422349"],"is_preprint":false},{"year":2025,"finding":"STEAP4 is ubiquitinated via K48-linked ubiquitin chains in obese visceral adipose tissue, leading to proteasomal degradation and reduced STEAP4 protein levels. Knockdown of STEAP4 in 3T3-L1 adipocytes impaired mitochondrial function.","method":"Combined proteomics and ubiquitylome mass spectrometry of visceral adipose tissue, siRNA knockdown, mitochondrial function assay","journal":"Molecular & cellular proteomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased mass spectrometry identification of K48 ubiquitination site with functional validation of knockdown effect, single lab","pmids":["41317904"],"is_preprint":false}],"current_model":"STEAP4 (STAMP2/TIARP) is a six-transmembrane, NADPH-dependent metalloreductase that reduces Fe³⁺ to Fe²⁺ and Cu²⁺ to Cu⁺ at the cell surface, endosomes, and mitochondria via an interdomain flavin-binding site; it integrates inflammatory and metabolic signaling by controlling cellular iron/copper homeostasis, NADPH levels, and ROS production, with its transcription regulated by STAT3, C/EBPα/β, FOXO1, GATA3, and SOX2, its protein stability controlled by HERP/ubiquitin and SIRT3-mediated deacetylation at K404 for mitochondrial targeting, and its downstream effects including modulation of Akt/mTOR, NF-κB, NRF2-NQO1, and integrated stress response (ATF4) pathways in metabolic tissues, immune cells, and cancer."},"narrative":{"mechanistic_narrative":"STEAP4 (STAMP2/TIARP) is a six-transmembrane metalloreductase that integrates metal homeostasis with inflammatory and metabolic signaling across adipose, immune, hepatic, skeletal, and cancer cells [PMID:17482547, PMID:22704678]. Its oxidoreductase domain harbors a novel interdomain flavin-binding site that shuttles electrons from NADPH to reduce extracytoplasmic Fe³⁺ and Cu²⁺, with kinetics retained at acidic pH consistent with activity at intracellular organelles [PMID:23733181]. Through this ferric/cupric reductase activity STEAP4 controls cellular ferrous iron, cuprous copper, NADPH, and ROS levels, and these metal/redox outputs are the proximal cause of its diverse biology: reduced iron and ROS drive CREB-dependent osteoclast differentiation [PMID:23990467], while loss of STEAP4 elevates NADPH and exaggerates macrophage inflammation, a defect rescued by wild-type but not reductase-dead protein [PMID:22704678]. Germline deletion produces spontaneous insulin resistance, dyslipidemia, fatty liver, and visceral adipose inflammation, establishing STEAP4 as essential for systemic metabolic homeostasis [PMID:17482547]. In metabolic tissues it enhances insulin-stimulated GLUT4 translocation and glucose uptake via Akt/PI3K signaling and stabilizes IRS-1 [PMID:21468601, PMID:25646886], and SIRT3-mediated deacetylation at K404 directs STEAP4 to mitochondria where it supports respiratory chain function and TCA-versus-glycolytic balance [PMID:41840161, PMID:39995871]. STEAP4 acts as a key effector downstream of inflammatory cytokines: IL-17 induces STEAP4-dependent copper uptake that activates XIAP and NF-κB to drive colitis-associated tumorigenesis [PMID:32060280], and STEAP4 is a Th17-specific effector in CNS-resident cells during autoimmune encephalomyelitis [PMID:33879167]. In cancer its iron-reductase-driven ROS modulates ATF4, NRF2-NQO1, and AKT/mTOR pathways, with both tumor-promoting and tumor-suppressive outcomes depending on context [PMID:25680860, PMID:40205952, PMID:38111065]. STEAP4 transcription is controlled by an extensive regulatory network including STAT3 and C/EBPα/β, FOXO1, GATA3, SOX2, and NF-κB/REL [PMID:20304921, PMID:23262293, PMID:37506793, PMID:41422349, PMID:40877891, PMID:41115643], while its protein abundance is set by K48-linked ubiquitin-proteasomal degradation that is opposed by HERP-mediated stabilization [PMID:41317904, PMID:41249464].","teleology":[{"year":2001,"claim":"Established STEAP4 as a cytokine-responsive transmembrane protein, first linking it to TNF-alpha signaling and adipocyte differentiation before any enzymatic function was known.","evidence":"Differential display, Northern blot, and immunofluorescence in TNF-alpha-treated 3T3-L1 adipocytes","pmids":["11443137"],"confidence":"Medium","gaps":["No molecular activity assigned","Mechanism of cytokine responsiveness not defined"]},{"year":2005,"claim":"Mapped STEAP4 subcellular distribution to Golgi, plasma membrane, endosomal and caveolar compartments and tied its expression to androgen signaling, raising a candidate role in prostate cancer growth.","evidence":"GFP live-cell imaging, confocal co-localization with EEA1 and caveolin-1, androgen treatment and colony assays in prostate cells/adipocytes","pmids":["15897894","15836432"],"confidence":"Medium","gaps":["Co-localization is correlative","EEA1 association later refuted by FRET","No enzymatic mechanism for growth effect"]},{"year":2007,"claim":"Demonstrated that STEAP4 is essential for systemic metabolic homeostasis, defining it as an integrator of inflammation and metabolism in vivo.","evidence":"Germline knockout mouse metabolic and inflammatory phenotyping","pmids":["17482547"],"confidence":"High","gaps":["Did not identify the biochemical activity underlying the phenotype","Tissue-of-origin of metabolic defect unresolved"]},{"year":2010,"claim":"Connected STEAP4 function to insulin action, showing it enhances insulin-stimulated glucose uptake, and identified STAT3 and C/EBP-alpha as direct transcriptional inputs.","evidence":"Glucose uptake assays with overexpression in human adipocytes; ChIP and reporter assays in mouse liver with IL-6/STAT3","pmids":["20127040","20304921"],"confidence":"High","gaps":["Glucose uptake mechanism not yet linked to a defined signaling node","Cytokine-to-promoter wiring described in liver only"]},{"year":2012,"claim":"Established the reductase activity as the cause of STEAP4's anti-inflammatory function by showing NADPH homeostasis controls macrophage inflammation and atherosclerosis protection.","evidence":"Knockout macrophages, NADPH measurement, reductase-deficient mutant rescue, bone marrow transplantation atherosclerosis model","pmids":["22704678","22244520"],"confidence":"High","gaps":["Direct enzymatic substrate in cells not measured","Link between NADPH pool and inflammatory output incompletely defined"]},{"year":2013,"claim":"Solved the oxidoreductase domain structure and defined STEAP4 as a flavin-dependent NADPH metalloreductase with physiological Fe(3+)/Cu(2+) kinetics, providing the biochemical basis for all downstream metal/redox biology.","evidence":"X-ray crystallography, in vitro kinetics, site-directed mutagenesis; parallel ferrireductase loss-of-function in osteoclasts","pmids":["23733181","23990467"],"confidence":"High","gaps":["Full-length transmembrane structure not solved","In vivo electron donor/acceptor topology not directly visualized"]},{"year":2015,"claim":"Resolved the hepatic and cancer arms of STEAP4 biology, showing it stabilizes IRS-1 to protect insulin signaling and that its iron-reductase-driven ROS/NADPH depletion engages ATF4 to control tumor growth.","evidence":"Co-IP, protein stability assays, bidirectional in vivo manipulation; ROS/NADPH measurement, knockdown, and nanoliposomal siRNA xenograft models","pmids":["25646886","23095254","25680860"],"confidence":"Medium","gaps":["IRS-1 stabilization mechanism (direct vs indirect) unresolved","ATF4 induction shown to be partial mediator only"]},{"year":2017,"claim":"Localized a pathogenic STEAP4 activity to mitochondria, showing hypoxia-induced STEAP4 dysregulates mitochondrial iron to drive ROS, colitis, and tumorigenesis.","evidence":"Unbiased proteomics, mouse colitis and colitis-associated cancer models, mitochondrial iron chelation rescue","pmids":["29078383"],"confidence":"High","gaps":["Mechanism of mitochondrial targeting not yet defined here","How mitochondrial iron is delivered to STEAP4 unclear"]},{"year":2020,"claim":"Defined STEAP4 as an inducible copper reductase in inflammatory signaling, placing it downstream of IL-17 to drive XIAP/NF-kB activation and tumorigenesis, and connected it to hepatic iron export.","evidence":"Gene knockout, copper measurement, XIAP/NF-kB/caspase assays, colitis-associated tumor model; FGF21/ferroportin hepatic studies","pmids":["32060280","32721044"],"confidence":"High","gaps":["Direct copper transfer to XIAP not demonstrated","Ferroportin regulation mechanism downstream of STEAP4 indirect"]},{"year":2021,"claim":"Established STEAP4 as a cell-type-specific, Th17-pathway effector in vivo using conditional deletion, distinguishing its inflammatory roles by lineage.","evidence":"Global and Nestin-Cre conditional knockout mice in active and passive Th17/Th1 EAE","pmids":["33879167"],"confidence":"High","gaps":["Molecular effector mechanism in CNS-resident cells not defined","Link to metalloreductase activity not directly tested"]},{"year":2023,"claim":"Expanded the transcriptional control of STEAP4 and dissected context-dependent AKT/mTOR coupling, showing STEAP4 can either inhibit or sustain AKT signaling depending on cell type.","evidence":"FOXO1 ChIP and promoter mutagenesis; co-IP and pharmacological rescue (SC79/MK2206) in HCC and prostate epithelial cells","pmids":["37506793","38111065","37866665"],"confidence":"Medium","gaps":["Opposing AKT effects across tissues unreconciled","Physical STEAP4-AKT interaction shown by single Co-IP"]},{"year":2025,"claim":"Defined STEAP4 protein-level control and additional roles in mitochondrial integrity, lysosomal iron handling, and redox-driven transcription, while broadening its regulatory network.","evidence":"HERP/ubiquitin and K48-ubiquitylome mass spectrometry; adipocyte- and liver-conditional KO with interactome/RNA-seq/lysosomal fractionation; ROS/NRF2-NQO1 and NRF2/NOTCH1 pathway dissection; GATA3, SOX2, REL, NAMPT-SIRT1-C/EBP-beta transcriptional studies","pmids":["41249464","41317904","39995871","41838890","40205952","41276039","41422349","40877891","41115643","41324246","41201016"],"confidence":"High","gaps":["Some ROS effects reported as independent of canonical ferric reductase activity, not mechanistically reconciled","Mitochondrial vs lysosomal iron pools handled by STEAP4 not unified","RNA splicing interactome role uncharacterized mechanistically"]},{"year":2026,"claim":"Identified post-translational control of STEAP4 mitochondrial targeting via SIRT3 deacetylation at K404, linking acetylation status to metabolic fate and cuproptosis sensitivity.","evidence":"Site-specific K404 mutagenesis, deacetylation assay, mitochondrial fractionation, metabolic flux, HBx mouse and orthotopic HCC models","pmids":["41840161"],"confidence":"High","gaps":["Acetyltransferase opposing SIRT3 not identified","Generality of K404 regulation beyond HCC unknown"]},{"year":null,"claim":"How STEAP4 partitions its single reductase activity among plasma membrane, endosomal/lysosomal, and mitochondrial pools to produce tissue- and context-specific (protective vs pathogenic) outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified model linking subcellular localization to metal/redox output and downstream pathway selection","Reductase-independent antioxidant effects reported but mechanistically unexplained","Direct in vivo substrate flux at each organelle not measured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[0,2,3,13,19,35]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[6,7,8]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[6]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[3,16]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[5,33,36]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[16,37]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,10,12,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,4,23]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[13,35,34]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,13,35,26]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[11,20,25,42,40,39]}],"complexes":[],"partners":["FAK","AKT","HBX","XIAP","HERP","SIRT3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q687X5","full_name":"Metalloreductase STEAP4","aliases":["Six-transmembrane epithelial antigen of prostate 4","SixTransMembrane protein of prostate 2","Tumor necrosis factor, alpha-induced protein 9"],"length_aa":459,"mass_kda":52.0,"function":"Integral membrane protein that functions as a NADPH-dependent ferric-chelate reductase, using NADPH from one side of the membrane to reduce a Fe(3+) chelate that is bound on the other side of the membrane. Mediates sequential transmembrane electron transfer from NADPH to FAD and onto heme, and finally to the Fe(3+) chelate (PubMed:30337524). Can also reduce Cu(2+) to Cu(1+) (By similarity). Plays a role in systemic metabolic homeostasis, integrating inflammatory and metabolic responses (By similarity). Associated with obesity and insulin-resistance (PubMed:18381574, PubMed:18430367). Involved in inflammatory arthritis, through the regulation of inflammatory cytokines (PubMed:19660107). Inhibits anchorage-independent cell proliferation (PubMed:19787193)","subcellular_location":"Cell membrane; Golgi apparatus membrane; Early endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q687X5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STEAP4","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/STEAP4","total_profiled":1310},"omim":[{"mim_id":"611098","title":"STEAP4 METALLOREDUCTASE; STEAP4","url":"https://www.omim.org/entry/611098"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":106.6}],"url":"https://www.proteinatlas.org/search/STEAP4"},"hgnc":{"alias_symbol":["FLJ23153","TIARP","STAMP2","SchLAH"],"prev_symbol":["TNFAIP9"]},"alphafold":{"accession":"Q687X5","domains":[{"cath_id":"3.40.50.720","chopping":"20-195","consensus_level":"high","plddt":93.101,"start":20,"end":195},{"cath_id":"1.20.120","chopping":"201-452","consensus_level":"high","plddt":94.3904,"start":201,"end":452}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q687X5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q687X5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q687X5-F1-predicted_aligned_error_v6.png","plddt_mean":90.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STEAP4","jax_strain_url":"https://www.jax.org/strain/search?query=STEAP4"},"sequence":{"accession":"Q687X5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q687X5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q687X5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q687X5"}},"corpus_meta":[{"pmid":"17482547","id":"PMC_17482547","title":"Coordinated 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proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/41317904","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":51789,"output_tokens":11114,"usd":0.161039,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22309,"output_tokens":4956,"usd":0.117722,"stage2_stop_reason":"end_turn"},"total_usd":0.278761,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of the Steap4 oxidoreductase domain was determined, revealing a novel interdomain flavin-binding site that shuttles electrons between the oxidoreductase and transmembrane domains. Detailed kinetic analysis showed physiologically relevant Km values for Fe(3+) and Cu(2+), flavin-dependent NADPH oxidase activity greater than Steap3, and retained activity at acidic pH suggesting intracellular organelle function. Structure-function mutagenesis showed disordered N-terminal residues do not contribute to enzymatic activity.\",\n      \"method\": \"X-ray crystallography, in vitro kinetic assay, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure solved with functional kinetic characterization and mutagenesis in single rigorous study\",\n      \"pmids\": [\"23733181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"STAMP2 (STEAP4) acts as a critical integrator of inflammatory and metabolic responses in adipocytes. STAMP2-knockout mice on a regular diet develop spontaneous insulin resistance, glucose intolerance, mild hyperglycemia, dyslipidemia, and fatty liver disease with overt visceral adipose tissue inflammation, establishing STAMP2 as essential for metabolic homeostasis.\",\n      \"method\": \"Germline knockout mouse model, metabolic phenotyping, inflammatory marker analysis\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined metabolic and inflammatory phenotypes, highly cited foundational study\",\n      \"pmids\": [\"17482547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Stamp2 controls macrophage inflammation through NADPH homeostasis: absence of Stamp2 results in significantly elevated cellular NADPH levels, and the exaggerated inflammatory response in Stamp2-/- macrophages is rescued by wild-type but not reductase-deficient Stamp2. Chemical and genetic suppression of NADPH production in Stamp2-/- macrophages reverts the heightened inflammatory response. Bone marrow transplantation confirmed Stamp2 in myeloid cells is sufficient to protect against atherosclerosis.\",\n      \"method\": \"Knockout macrophages, NADPH measurement, reductase-deficient mutant rescue, bone marrow transplantation, atherosclerosis model\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods including mutant rescue, genetic epistasis via BMT, and metabolite measurement\",\n      \"pmids\": [\"22704678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Steap4 functions as an endosomal ferrireductase in osteoclasts. Knockdown of Steap4 by lentivirus-mediated shRNA inhibits osteoclast formation in vitro and decreases cellular ferrous iron, reactive oxygen species, and activation of CREB, a transcription factor required for osteoclast differentiation downstream of RANKL-induced calcium signaling.\",\n      \"method\": \"Lentivirus-mediated shRNA knockdown, ferrous iron measurement, ROS assay, CREB phosphorylation assay, osteoclast differentiation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean loss-of-function with multiple biochemical readouts in a defined cellular differentiation context\",\n      \"pmids\": [\"23990467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IL-17 induces cellular copper uptake via induction of STEAP4 (a metalloreductase). Elevated intracellular copper activates the E3 ligase XIAP, which potentiates IL-17-induced NF-κB activation and suppresses caspase-3 activity. STEAP4 deficiency abrogated IL-17-induced copper uptake and colon tumor formation in a colitis-associated tumorigenesis model.\",\n      \"method\": \"Gene knockout mouse model, copper measurement, XIAP activity assay, NF-κB reporter, caspase-3 activity assay, colitis-associated tumorigenesis model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with multiple biochemical pathway readouts and in vivo tumor model\",\n      \"pmids\": [\"32060280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"STEAP4 is a ferrireductase induced by hypoxia in colitis; its expression leads to dysregulation of mitochondrial iron balance and enhanced reactive oxygen species production, increasing susceptibility to colitis and promoting colon tumor formation. Mitochondrial iron chelation therapy improved colitis, establishing mitochondrial iron dysregulation as a key mechanism.\",\n      \"method\": \"Unbiased proteomics, mouse colitis model, colitis-associated cancer model, mitochondrial iron chelation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multi-model in vivo approach with pharmacological and genetic validation of mitochondrial iron mechanism\",\n      \"pmids\": [\"29078383\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"STAMP2 (STEAP4) localizes primarily to the Golgi complex, trans-Golgi network, plasma membrane, and vesicular-tubular cytosolic structures. It co-localizes with Early Endosome Antigen 1 (EEA1), suggesting involvement in secretory/endocytic pathways. Expression is androgen-regulated in androgen receptor-positive LNCaP cells but not in AR-negative PC-3 or DU145 cells. Ectopic expression increases prostate cancer cell growth and colony formation.\",\n      \"method\": \"GFP-fusion live-cell imaging, immunofluorescence confocal microscopy, co-localization with EEA1, androgen treatment assays, colony formation assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct localization experiments with functional growth assay, single lab\",\n      \"pmids\": [\"15897894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"TIARP (STEAP4) is a TNF-alpha-inducible transmembrane protein that emerges at the plasma membrane during adipocyte differentiation. Commitment to the differentiation process is required for cytokine responsiveness, and differentiation itself induces sharp TIARP mRNA expression.\",\n      \"method\": \"Differential display, immunofluorescence, Northern blot, TNF-alpha treatment of 3T3-L1 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct expression and localization experiments, replicated for TNF-alpha regulation, single lab\",\n      \"pmids\": [\"11443137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"TIARP (STEAP4) co-localizes with caveolin-1 as patches at the plasma membrane of 3T3-L1 adipocytes, detected by confocal microscopy. Immunoblot analysis showed TIARP is completely detergent-extractible from membranes, whereas caveolin-1 is present in both extractible and -insoluble pools, indicating TIARP partitions within caveolae signaling domains.\",\n      \"method\": \"Confocal microscopy co-localization, detergent extraction fractionation, immunoblot\",\n      \"journal\": \"Biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct co-localization and biochemical fractionation, single lab with two methods\",\n      \"pmids\": [\"15836432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"STEAP4 associates with focal adhesion kinase (FAK) and regulates FAK activity through Y397 phosphorylation. STEAP4 expression inhibits anchorage-independent cell growth. CpG sequences in the STEAP4 promoter are frequently methylated in androgen-independent DU145 prostate cancer cells, and demethylation treatment induces STEAP4 expression.\",\n      \"method\": \"Co-immunoprecipitation, FAK phosphorylation assay, soft agar colony assay, methylation-specific PCR, demethylation treatment\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP with functional phosphorylation readout, single lab, single method for interaction\",\n      \"pmids\": [\"19787193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"STEAP4 promotes insulin-stimulated glucose uptake in mature human adipocytes. Overexpression of STEAP4 does not affect adipogenesis but enhances 2-deoxy-D-glucose uptake in a PI3K-dependent manner. Expression is regulated by adipokines TNF-alpha, IL-6, and leptin.\",\n      \"method\": \"2-deoxy-D-[3H]-glucose uptake assay, oil red O staining, Western blotting, RT-PCR\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct functional glucose uptake assay with overexpression, single lab\",\n      \"pmids\": [\"20127040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Hepatic STEAP4 transcription is a direct target of phosphorylated STAT3 in mouse liver, induced by IL-6. In addition, CCAAT/enhancer-binding protein alpha (C/EBPα) is required for STEAP4 regulation during feeding/fasting and obesity, acting in concert with STAT3; both factors bind the proximal steap4 promoter in vivo.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), luciferase reporter assay, IL-6 treatment, STAT3 phosphorylation analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP in vivo with promoter reporter assays and genetic intervention, multiple orthogonal methods\",\n      \"pmids\": [\"20304921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"siRNA-mediated STEAP4 knockdown significantly decreases insulin-stimulated glucose transport in human adipocytes by reducing GLUT4 translocation to the plasma membrane via attenuated Akt phosphorylation. STEAP4 does not interact with EEA1 (confirmed by FRET analysis) and does not alter EEA1 protein expression, establishing that the effect on glucose uptake is EEA1-independent.\",\n      \"method\": \"siRNA knockdown, 2-deoxy-glucose uptake assay, GLUT4 translocation assay, Akt phosphorylation western blot, FRET analysis\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with defined molecular pathway readout, two orthogonal methods (functional + FRET), single lab\",\n      \"pmids\": [\"21468601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"STAMP2 increases reactive oxygen species through its iron reductase activity, which also depletes NADPH levels in prostate cancer cells. Knockdown inhibits proliferation, colony formation, anchorage-independent growth, and increases apoptosis. STAMP2 effects are mediated at least in part through ATF4, whose expression is regulated by ROS. Systemic nanoliposomal siRNA silencing of STAMP2 profoundly inhibited PCa tumor growth in two preclinical models.\",\n      \"method\": \"ROS measurement, NADPH assay, shRNA/siRNA knockdown, in vitro proliferation/apoptosis assays, xenograft models, nanoliposomal siRNA delivery\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods with in vitro and in vivo validation of iron reductase-mediated ROS/NADPH mechanism\",\n      \"pmids\": [\"25680860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Hepatic STAMP2 physically interacts with and decreases the stability of hepatitis B virus X protein (HBx), counteracting HBx-induced hepatic lipid accumulation and insulin resistance. STAMP2 prevented HBx-induced degradation of IRS1 protein and restored insulin-mediated inhibition of gluconeogenic enzyme expression.\",\n      \"method\": \"Co-immunoprecipitation, protein stability assay, HBx transgenic mouse analysis, Western blot for IRS1 and gluconeogenic enzymes\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP demonstrating physical interaction with functional protein stability and signaling readouts, single lab\",\n      \"pmids\": [\"23095254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Hepatic STAMP2 modulates insulin sensitivity via IRS-1 stability. Knockdown of hepatic STAMP2 by siRNA accelerated hepatic steatosis and insulin resistance in HFD mice; adenoviral STAMP2 delivery improved hepatic steatosis and counteracted oleic acid-induced insulin resistance by modulating IRS-1 stability.\",\n      \"method\": \"In vivo siRNA knockdown, adenoviral overexpression, glucose/insulin tolerance tests, IRS-1 protein stability assay, in vitro NAFLD model\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — bidirectional manipulation (KD + OE) in vivo and in vitro with defined molecular mechanism, single lab\",\n      \"pmids\": [\"25646886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STEAP4 is induced by TNF-alpha in fibroblast-like synoviocytes (FLS) and localizes to endosomal/lysosomal compartments. STEAP4 downregulation by siRNA enhanced IL-6 mRNA expression; overexpression suppressed IL-6 and IL-8 expression, inhibited cell proliferation, and induced apoptosis via caspase-3 in FLS.\",\n      \"method\": \"siRNA knockdown, plasmid overexpression, IL-6/IL-8 ELISA, proliferation assay, caspase-3 apoptosis assay, immunofluorescence localization\",\n      \"journal\": \"Modern rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — bidirectional manipulation with multiple functional readouts and subcellular localization, single lab\",\n      \"pmids\": [\"21633911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"STEAP4 overexpression in neutrophil-like HL60 cells down-regulates neutrophil migration in a transwell assay. TIARP/STEAP4-deficient neutrophils overexpress CXCR1 and CXCR2 and show enhanced migration activity facilitated by CXCL2 in vitro and in vivo.\",\n      \"method\": \"GFP-STEAP4 overexpression, transwell migration assay, DNA microarray of TIARP-/- neutrophils, in vivo K/BxN serum transfer arthritis model\",\n      \"journal\": \"Clinical and experimental rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct functional migration assay with genetic KO microarray validation, single lab\",\n      \"pmids\": [\"22244520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TIARP (STEAP4) attenuates arthritis by independently down-regulating CXCL2 and IL-6 production by fibroblast-like synoviocytes and reducing CXCR1/CXCR2 expression in neutrophils, reducing neutrophil migration into arthritic joints. IL-6R blockade significantly attenuated arthritis in TIARP-/- mice with diminished neutrophil recruitment.\",\n      \"method\": \"TIARP-/- mouse K/BxN serum transfer model, DNA microarray, in vitro neutrophil migration assay, anti-IL-6R antibody blockade, immunohistochemistry\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse model with pharmacological rescue and in vitro mechanistic validation, single lab\",\n      \"pmids\": [\"27995997\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ER stress (induced by thapsigargin or tunicamycin) significantly reduces STAMP2 mRNA and protein expression and alters its intracellular localization in adipocytes, reducing total iron reductase activity. TNF-alpha has the opposite effect. Promoter analysis by reporter assays and ChIP showed that ER stress disrupts C/EBPα-mediated STAMP2 transcription.\",\n      \"method\": \"ER stress inducers, iron reductase activity assay, luciferase promoter reporter, ChIP assay, immunofluorescence localization\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity measurement plus ChIP and reporter assays linking ER stress to C/EBPα-STAMP2 axis, single lab\",\n      \"pmids\": [\"30710574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"C/EBPβ directly regulates STEAP4 gene transcription by binding the C/EBPβ binding motif at -73/-59 bp of the STEAP4 promoter, as demonstrated by progressive deletions, site-directed mutations of the promoter construct, and ChIP assays. C/EBPβ protein levels increase with LPS treatment in parallel with STEAP4 and its splice variant induction.\",\n      \"method\": \"Promoter deletion constructs, site-directed mutagenesis, luciferase reporter assay, chromatin immunoprecipitation (ChIP)\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary promoter methods (deletion + mutation + ChIP) in single study, single lab\",\n      \"pmids\": [\"23262293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Articular chondrocytes gain resistance to lipotoxicity through a PKCK2-STAMP2-FSP27 signaling cascade that promotes lipid droplet accumulation, sequestering free fatty acids. Lipid droplet accumulation confers resistance to oleate-induced lipotoxicity; when FFAs are freed from lipid droplets, lipotoxicity occurs regardless of saturation status.\",\n      \"method\": \"HFD-induced OA mouse model, in vitro chondrocyte treatment, lipid droplet quantification, PKCK2 inhibition, STAMP2 and FSP27 knockdown/overexpression\",\n      \"journal\": \"Bone research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro models with genetic manipulation of pathway components, single lab\",\n      \"pmids\": [\"30002945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"AMPK functions upstream of STAMP2 to regulate its expression. Cilostazol activates AMPK in vivo and in vitro, which drives transcriptional upregulation of STAMP2, reversing HFD- and oleic acid-induced STAMP2 downregulation and ameliorating hepatic steatosis.\",\n      \"method\": \"HFD mouse model, HepG2 cells, AMPK inhibitors/activators, Western blot, qPCR, in vivo and in vitro STAMP2 expression analysis\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pharmacological and genetic epistasis placing AMPK upstream of STAMP2, replicated in vivo and in vitro, single lab\",\n      \"pmids\": [\"30366981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STEAP4 is a downstream effector molecule specifically in the IL-17/Th17 signaling pathway in the CNS. STEAP4 knockout mice are resistant to Th17- but not Th1-induced experimental autoimmune encephalomyelitis (EAE); ablation of STEAP4 specifically in CNS-resident cells (Nestin-Cre STEAP4fl/fl) attenuated disease in both active and passive Th17 EAE.\",\n      \"method\": \"Global and conditional (Nestin-Cre) STEAP4 knockout mice, active immunization EAE, passive Th17/Th1 transfer EAE, microarray analysis\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with cell-type-specific rescue establishes CNS-resident cell STEAP4 as Th17-specific effector, multiple genetic approaches\",\n      \"pmids\": [\"33879167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Stamp2-deficient mice after myocardial ischemia-reperfusion, augmented neutrophil infiltration produces excess ROS activating the redox-sensitive p38 MAPK, driving fibroblast-to-myofibroblast transdifferentiation and cardiac fibrosis. Antibody-mediated neutrophil depletion in Stamp2-/- mice reduced deterioration of cardiac function to WT levels, establishing PMN as the key cellular mediator.\",\n      \"method\": \"Stamp2-/- mouse I/R model, echocardiography, histology, ROS measurement, p38 MAPK assay, MPO measurement, neutrophil depletion antibody\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with rescue by neutrophil depletion establishing mechanism, single lab\",\n      \"pmids\": [\"34691017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXO1 directly binds to the promoter regions of CD36 and STEAP4 genes and regulates their transcriptional activities, as confirmed by chromatin immunoprecipitation (ChIP) and site-directed mutagenesis of promoter binding sites in bovine adipocytes.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), site-directed mutagenesis, luciferase reporter assay, siRNA knockdown\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP plus promoter mutagenesis validating FOXO1 as direct transcriptional regulator of STEAP4, single lab\",\n      \"pmids\": [\"37506793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STEAP4 physically interacts with AKT and inhibits the PI3K/AKT pathway, suppressing cisplatin resistance in hepatocellular carcinoma. Double knockdown of STEAP4 and AKT significantly inhibited cisplatin resistance, and STEAP4 expression negatively correlates with PI3K/AKT pathway activity in clinical specimens.\",\n      \"method\": \"Co-immunoprecipitation, siRNA double knockdown, cell viability/colony/apoptosis assays, xenograft tumor model, clinical specimen correlation\",\n      \"journal\": \"Cancer & metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP for interaction plus functional rescue experiment and in vivo validation, single lab\",\n      \"pmids\": [\"38111065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STEAP4 regulates proliferation and apoptosis of prostate epithelial cells (BPH context) through the AKT/mTOR signaling pathway. STEAP4 knockdown induces apoptosis and inhibits cell survival; AKT/mTOR activator SC79 reverses STEAP4 knockdown-induced apoptosis, and AKT/mTOR inhibitor MK2206 reduces STEAP4 OE-induced viability increase.\",\n      \"method\": \"siRNA knockdown, overexpression, CCK-8 assay, flow cytometry, SC79/MK2206 pharmacological rescue, Western blot for AKT/mTOR pathway\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pharmacological rescue experiments placing STEAP4 upstream of AKT/mTOR, single lab\",\n      \"pmids\": [\"37866665\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Recombinant FGF21 ameliorates hepatic steatosis and insulin resistance through upregulation of STAMP2 expression, and improves hepatic iron overload (HIO) through hepatic STAMP2-mediated upregulation of ferroportin expression, an iron exporter.\",\n      \"method\": \"HFD mouse model, human NAFLD samples, HepG2 cells, adenoviral STAMP2 overexpression, ferroportin Western blot, iron measurement\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro models with defined molecular target (ferroportin), single lab\",\n      \"pmids\": [\"32721044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"STAMP2 is required for human adipose-derived stem cell (ASC) differentiation into adipocytes. shRNA-mediated STAMP2 knockdown in ASCs significantly suppresses adipogenesis and impairs optimal expression of adipogenic genes and adipocyte metabolic function. ASC-derived adipocyte-mediated stimulation of prostate tumor growth in nude mice is significantly reduced upon STAMP2 knockdown.\",\n      \"method\": \"shRNA knockdown in human ASCs, adipogenesis assay, adipogenic gene expression, nude mouse co-implantation tumor model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in human primary cells with in vivo tumor growth readout, single lab\",\n      \"pmids\": [\"29190878\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STAMP2 suppresses autophagy in prostate cancer cells through modulation of the integrated stress response axis (ATF4 pathway). STAMP2 also regulates mitochondrial respiration.\",\n      \"method\": \"STAMP2 knockdown/overexpression, autophagy flux assay, mitochondrial respiration measurement (Seahorse)\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assays without detailed mechanistic dissection of the pathway, single lab, limited methods described in abstract\",\n      \"pmids\": [\"35141021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HERP interacts with STEAP4 to prevent its ubiquitin-mediated proteasomal degradation, stabilizing STEAP4 protein. HERP regulates adipogenesis through STEAP4 in a PPARγ-dependent manner. Enhancing STEAP4 expression ameliorated adipose expansion and metabolic disorders in HERP-KO mice.\",\n      \"method\": \"Co-immunoprecipitation, HERP KO mouse, STEAP4 ubiquitination assay, PPARγ pathway analysis, adenoviral STEAP4 rescue\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP plus functional rescue in KO mice with PPARγ pathway linkage, single lab\",\n      \"pmids\": [\"41249464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STEAP4 promotes intracellular Fe2+ accumulation and ROS elevation, upregulating C/EBPβ expression. C/EBPβ in turn binds a functional site in the Steap4 promoter and upregulates Steap4, establishing a self-amplifying Steap4/Fe2+-ROS/C/EBPβ positive feedback loop. Knockdown of Steap4 or C/EBPβ suppressed BMSC adipocyte differentiation.\",\n      \"method\": \"Knockdown studies, C/EBPβ promoter binding assay, Fe2+ measurement, ROS assay, adipogenic differentiation assay, deferoxamine treatment in vivo\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — bidirectional genetic manipulation with promoter interaction and iron/ROS measurements, single lab\",\n      \"pmids\": [\"41201016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"SIRT3 deacetylates STEAP4 at lysine 404, which is required for its mitochondrial targeting. HBx attenuates SIRT3, impairing STEAP4 deacetylation and abolishing its mitochondrial localization. Loss of mitochondrial STEAP4 drives a switch from TCA cycle respiration to glycolysis, reducing cuproptosis sensitivity. Restoring STEAP4 or activating SIRT3 with honokiol re-instates mitochondrial STEAP4 and re-sensitizes HBV-related HCC cells to cuproptosis.\",\n      \"method\": \"Deacetylation assay, site-specific mutagenesis (K404), mitochondrial fractionation, metabolic flux analysis, HBx-transgenic mice, pharmacological SIRT3 activation, orthotopic HCC model\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — specific acetylation site identified by mutagenesis, mitochondrial targeting linked mechanistically to deacetylation, multiple in vivo and in vitro models\",\n      \"pmids\": [\"41840161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STEAP4 reduces intracellular ROS by selectively enhancing activities of antioxidant enzymes SOD and GPX, independently of its canonical ferric reductase function. The consequent ROS reduction inhibits NRF2 nuclear translocation, suppressing NOTCH1 transcription through direct NRF2 promoter binding; restoring ROS levels reversed this inhibitory effect in TNBC cells.\",\n      \"method\": \"ROS measurement, SOD/GPX activity assays, NRF2 nuclear translocation assay, NOTCH1 promoter assay, NRF2 ChIP-like analysis, overexpression/knockdown\",\n      \"journal\": \"International journal of biological macromolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — enzymatic activity measurements plus nuclear translocation assays and promoter binding establishing ROS/NRF2/NOTCH1 pathway, single lab\",\n      \"pmids\": [\"41276039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STEAP4 knockout significantly reduces colon tumorigenesis in a genetically engineered mouse model. STEAP4 knockdown attenuates the NRF2-NQO1 signaling pathway in colon cancer cells, inducing apoptosis and autophagy. STEAP4 overexpression amplifies ROS production and activates NRF2-NQO1 in a ferric iron (Fe3+)-dependent manner. NQO1-bioactivatable drugs are highly effective at eradicating STEAP4-overexpressing colon cancer cells.\",\n      \"method\": \"Genetically engineered KO mouse model, shRNA knockdown, STEAP4 overexpression, ROS assay, NRF2/NQO1 pathway analysis, xenograft growth assay, NQO1-targeted drug treatment\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in vivo with mechanistic dissection of Fe3+-dependent ROS/NRF2-NQO1 axis in vitro and in vivo, multiple orthogonal approaches\",\n      \"pmids\": [\"40205952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Adipocyte-specific Steap4 deficiency impairs respiratory chain complex activity and causes mitochondrial dysfunction in white adipose tissue. Mass spectrometry identified STEAP4 interactomes as mitochondrial proteins and RNA splicing proteins; Steap4 deficiency altered RNA splicing patterns with enriched mitochondrial functions by RNA-seq. Brown adipocyte-specific Steap4 deficiency impaired mitochondrial function, increased brown fat whitening, reduced energy expenditure, and exacerbated insulin resistance.\",\n      \"method\": \"Adipocyte-conditional KO, mass spectrometry interactome, RNA-seq splicing analysis, respiratory chain complex activity assay, metabolic cage energy expenditure measurement\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with multi-omics (proteomics + RNA-seq) and direct mitochondrial function measurements, multiple orthogonal methods\",\n      \"pmids\": [\"39995871\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STEAP4 maintains lysosomal iron homeostasis and prevents lysosomal membrane damage. In liver-specific STEAP4 KO mice, APAP treatment caused iron buildup in endolysosomes, lysosomal membrane damage, release of cathepsin B, impaired mTOR activity, defective mitophagy, and reduced hepatocyte proliferation at 48h. STEAP4 is not essential during early injury but is critical for liver regeneration.\",\n      \"method\": \"Liver-specific KO (Alb-Cre Steap4fl/fl), APAP model, lysosomal fractionation, cathepsin B assay, mTOR signaling analysis, iron measurement, DFP chelation rescue\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with pharmacological rescue and defined subcellular (endolysosomal) iron mechanism with multiple functional readouts\",\n      \"pmids\": [\"41838890\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Lithium exposure upregulates FOXO1, which promotes FOXO1-mediated STEAP4 transcription. Upregulated STEAP4 elevates intracellular Cu+ levels causing cuproptosis in trophoblasts, inducing miscarriage. Therapeutic knockdown of FOXO1 or STEAP4, or Cu chelation with TTM, suppressed placental cuproptosis and alleviated miscarriage in Li-exposed mice.\",\n      \"method\": \"Mouse Li-exposure model, ChIP for FOXO1-STEAP4 promoter, Cu+ measurement, cuproptosis markers, AAV-mediated KD, TTM treatment\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-validated transcriptional axis with pharmacological and genetic rescue, single lab\",\n      \"pmids\": [\"40855689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"REL (a NF-κB subunit) enhances STEAP4 expression by binding to its promoter, as demonstrated by transcriptome analysis and in vitro cellular experiments in valvular interstitial cells. STEAP4-mediated iron overload drives ferroptosis contributing to aortic valve calcification.\",\n      \"method\": \"Transcriptome analysis, luciferase reporter or promoter binding assay, STEAP4 knockdown/overexpression in hVICs, ferroptosis inhibitor treatment, ApoE-/- HFD and wire-injury mouse models\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — REL-STEAP4 promoter interaction with in vivo and in vitro functional validation, single lab\",\n      \"pmids\": [\"41115643\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC2 directly interacts with SOX2 to inhibit its acetylation and destabilize the SOX2 protein. SOX2 binds to the STAMP2 promoter region and modulates its transcriptional activity. The HDAC2/SOX2/STAMP2 axis regulates macrophage activation in septic lung injury.\",\n      \"method\": \"Co-immunoprecipitation, luciferase assay, chromatin immunoprecipitation (ChIP), CLP mouse model, LPS-macrophage model\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for HDAC2-SOX2 interaction plus ChIP for SOX2-STAMP2 promoter binding, single lab\",\n      \"pmids\": [\"40877891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"NAMPT regulates STEAP4 expression through the SIRT1-C/EBPβ axis: NAMPT drives NAD+ synthesis enabling SIRT1 deacetylase activity, which deacetylates C/EBPβ to allow its function as a STEAP4 transcriptional activator. STEAP4 in turn upregulates NRF2 expression and nuclear translocation to combat oxidative stress in NAFLD.\",\n      \"method\": \"NAMPT/SIRT1 inhibition in HFD mice, C/EBPβ acetylation assay, STEAP4 promoter analysis, NRF2 nuclear translocation assay\",\n      \"journal\": \"Journal of molecular cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple components of signaling axis tested with pharmacological inhibition in vivo and biochemical assays, single lab\",\n      \"pmids\": [\"41324246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GATA3 transcriptionally activates STEAP4 by binding to its promoter, as confirmed by ChIP-PCR and dual-luciferase assays. STEAP4 knockdown inhibited Th2 differentiation and Th2-related cytokine production in vitro; STEAP4 knockdown rescued the promoting effects of GATA3 overexpression on Th2 differentiation, placing STEAP4 downstream of GATA3 in this pathway.\",\n      \"method\": \"ChIP-PCR, dual-luciferase reporter assay, siRNA knockdown, GATA3 overexpression, Th2 differentiation assay, OVA mouse model\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirming GATA3-STEAP4 promoter interaction with genetic epistasis (STEAP4 KD rescues GATA3 OE effect), single lab\",\n      \"pmids\": [\"41422349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STEAP4 is ubiquitinated via K48-linked ubiquitin chains in obese visceral adipose tissue, leading to proteasomal degradation and reduced STEAP4 protein levels. Knockdown of STEAP4 in 3T3-L1 adipocytes impaired mitochondrial function.\",\n      \"method\": \"Combined proteomics and ubiquitylome mass spectrometry of visceral adipose tissue, siRNA knockdown, mitochondrial function assay\",\n      \"journal\": \"Molecular & cellular proteomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased mass spectrometry identification of K48 ubiquitination site with functional validation of knockdown effect, single lab\",\n      \"pmids\": [\"41317904\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STEAP4 (STAMP2/TIARP) is a six-transmembrane, NADPH-dependent metalloreductase that reduces Fe³⁺ to Fe²⁺ and Cu²⁺ to Cu⁺ at the cell surface, endosomes, and mitochondria via an interdomain flavin-binding site; it integrates inflammatory and metabolic signaling by controlling cellular iron/copper homeostasis, NADPH levels, and ROS production, with its transcription regulated by STAT3, C/EBPα/β, FOXO1, GATA3, and SOX2, its protein stability controlled by HERP/ubiquitin and SIRT3-mediated deacetylation at K404 for mitochondrial targeting, and its downstream effects including modulation of Akt/mTOR, NF-κB, NRF2-NQO1, and integrated stress response (ATF4) pathways in metabolic tissues, immune cells, and cancer.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STEAP4 (STAMP2/TIARP) is a six-transmembrane metalloreductase that integrates metal homeostasis with inflammatory and metabolic signaling across adipose, immune, hepatic, skeletal, and cancer cells [#1, #2]. Its oxidoreductase domain harbors a novel interdomain flavin-binding site that shuttles electrons from NADPH to reduce extracytoplasmic Fe\\u00b3\\u207a and Cu\\u00b2\\u207a, with kinetics retained at acidic pH consistent with activity at intracellular organelles [#0]. Through this ferric/cupric reductase activity STEAP4 controls cellular ferrous iron, cuprous copper, NADPH, and ROS levels, and these metal/redox outputs are the proximal cause of its diverse biology: reduced iron and ROS drive CREB-dependent osteoclast differentiation [#3], while loss of STEAP4 elevates NADPH and exaggerates macrophage inflammation, a defect rescued by wild-type but not reductase-dead protein [#2]. Germline deletion produces spontaneous insulin resistance, dyslipidemia, fatty liver, and visceral adipose inflammation, establishing STEAP4 as essential for systemic metabolic homeostasis [#1]. In metabolic tissues it enhances insulin-stimulated GLUT4 translocation and glucose uptake via Akt/PI3K signaling and stabilizes IRS-1 [#12, #15], and SIRT3-mediated deacetylation at K404 directs STEAP4 to mitochondria where it supports respiratory chain function and TCA-versus-glycolytic balance [#33, #36]. STEAP4 acts as a key effector downstream of inflammatory cytokines: IL-17 induces STEAP4-dependent copper uptake that activates XIAP and NF-\\u03baB to drive colitis-associated tumorigenesis [#4], and STEAP4 is a Th17-specific effector in CNS-resident cells during autoimmune encephalomyelitis [#23]. In cancer its iron-reductase-driven ROS modulates ATF4, NRF2-NQO1, and AKT/mTOR pathways, with both tumor-promoting and tumor-suppressive outcomes depending on context [#13, #35, #26]. STEAP4 transcription is controlled by an extensive regulatory network including STAT3 and C/EBP\\u03b1/\\u03b2, FOXO1, GATA3, SOX2, and NF-\\u03baB/REL [#11, #20, #25, #42, #40, #39], while its protein abundance is set by K48-linked ubiquitin-proteasomal degradation that is opposed by HERP-mediated stabilization [#43, #31].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established STEAP4 as a cytokine-responsive transmembrane protein, first linking it to TNF-alpha signaling and adipocyte differentiation before any enzymatic function was known.\",\n      \"evidence\": \"Differential display, Northern blot, and immunofluorescence in TNF-alpha-treated 3T3-L1 adipocytes\",\n      \"pmids\": [\"11443137\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular activity assigned\", \"Mechanism of cytokine responsiveness not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mapped STEAP4 subcellular distribution to Golgi, plasma membrane, endosomal and caveolar compartments and tied its expression to androgen signaling, raising a candidate role in prostate cancer growth.\",\n      \"evidence\": \"GFP live-cell imaging, confocal co-localization with EEA1 and caveolin-1, androgen treatment and colony assays in prostate cells/adipocytes\",\n      \"pmids\": [\"15897894\", \"15836432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-localization is correlative\", \"EEA1 association later refuted by FRET\", \"No enzymatic mechanism for growth effect\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated that STEAP4 is essential for systemic metabolic homeostasis, defining it as an integrator of inflammation and metabolism in vivo.\",\n      \"evidence\": \"Germline knockout mouse metabolic and inflammatory phenotyping\",\n      \"pmids\": [\"17482547\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the biochemical activity underlying the phenotype\", \"Tissue-of-origin of metabolic defect unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Connected STEAP4 function to insulin action, showing it enhances insulin-stimulated glucose uptake, and identified STAT3 and C/EBP-alpha as direct transcriptional inputs.\",\n      \"evidence\": \"Glucose uptake assays with overexpression in human adipocytes; ChIP and reporter assays in mouse liver with IL-6/STAT3\",\n      \"pmids\": [\"20127040\", \"20304921\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Glucose uptake mechanism not yet linked to a defined signaling node\", \"Cytokine-to-promoter wiring described in liver only\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the reductase activity as the cause of STEAP4's anti-inflammatory function by showing NADPH homeostasis controls macrophage inflammation and atherosclerosis protection.\",\n      \"evidence\": \"Knockout macrophages, NADPH measurement, reductase-deficient mutant rescue, bone marrow transplantation atherosclerosis model\",\n      \"pmids\": [\"22704678\", \"22244520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct enzymatic substrate in cells not measured\", \"Link between NADPH pool and inflammatory output incompletely defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Solved the oxidoreductase domain structure and defined STEAP4 as a flavin-dependent NADPH metalloreductase with physiological Fe(3+)/Cu(2+) kinetics, providing the biochemical basis for all downstream metal/redox biology.\",\n      \"evidence\": \"X-ray crystallography, in vitro kinetics, site-directed mutagenesis; parallel ferrireductase loss-of-function in osteoclasts\",\n      \"pmids\": [\"23733181\", \"23990467\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length transmembrane structure not solved\", \"In vivo electron donor/acceptor topology not directly visualized\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved the hepatic and cancer arms of STEAP4 biology, showing it stabilizes IRS-1 to protect insulin signaling and that its iron-reductase-driven ROS/NADPH depletion engages ATF4 to control tumor growth.\",\n      \"evidence\": \"Co-IP, protein stability assays, bidirectional in vivo manipulation; ROS/NADPH measurement, knockdown, and nanoliposomal siRNA xenograft models\",\n      \"pmids\": [\"25646886\", \"23095254\", \"25680860\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IRS-1 stabilization mechanism (direct vs indirect) unresolved\", \"ATF4 induction shown to be partial mediator only\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Localized a pathogenic STEAP4 activity to mitochondria, showing hypoxia-induced STEAP4 dysregulates mitochondrial iron to drive ROS, colitis, and tumorigenesis.\",\n      \"evidence\": \"Unbiased proteomics, mouse colitis and colitis-associated cancer models, mitochondrial iron chelation rescue\",\n      \"pmids\": [\"29078383\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of mitochondrial targeting not yet defined here\", \"How mitochondrial iron is delivered to STEAP4 unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined STEAP4 as an inducible copper reductase in inflammatory signaling, placing it downstream of IL-17 to drive XIAP/NF-kB activation and tumorigenesis, and connected it to hepatic iron export.\",\n      \"evidence\": \"Gene knockout, copper measurement, XIAP/NF-kB/caspase assays, colitis-associated tumor model; FGF21/ferroportin hepatic studies\",\n      \"pmids\": [\"32060280\", \"32721044\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct copper transfer to XIAP not demonstrated\", \"Ferroportin regulation mechanism downstream of STEAP4 indirect\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established STEAP4 as a cell-type-specific, Th17-pathway effector in vivo using conditional deletion, distinguishing its inflammatory roles by lineage.\",\n      \"evidence\": \"Global and Nestin-Cre conditional knockout mice in active and passive Th17/Th1 EAE\",\n      \"pmids\": [\"33879167\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular effector mechanism in CNS-resident cells not defined\", \"Link to metalloreductase activity not directly tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded the transcriptional control of STEAP4 and dissected context-dependent AKT/mTOR coupling, showing STEAP4 can either inhibit or sustain AKT signaling depending on cell type.\",\n      \"evidence\": \"FOXO1 ChIP and promoter mutagenesis; co-IP and pharmacological rescue (SC79/MK2206) in HCC and prostate epithelial cells\",\n      \"pmids\": [\"37506793\", \"38111065\", \"37866665\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Opposing AKT effects across tissues unreconciled\", \"Physical STEAP4-AKT interaction shown by single Co-IP\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined STEAP4 protein-level control and additional roles in mitochondrial integrity, lysosomal iron handling, and redox-driven transcription, while broadening its regulatory network.\",\n      \"evidence\": \"HERP/ubiquitin and K48-ubiquitylome mass spectrometry; adipocyte- and liver-conditional KO with interactome/RNA-seq/lysosomal fractionation; ROS/NRF2-NQO1 and NRF2/NOTCH1 pathway dissection; GATA3, SOX2, REL, NAMPT-SIRT1-C/EBP-beta transcriptional studies\",\n      \"pmids\": [\"41249464\", \"41317904\", \"39995871\", \"41838890\", \"40205952\", \"41276039\", \"41422349\", \"40877891\", \"41115643\", \"41324246\", \"41201016\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Some ROS effects reported as independent of canonical ferric reductase activity, not mechanistically reconciled\", \"Mitochondrial vs lysosomal iron pools handled by STEAP4 not unified\", \"RNA splicing interactome role uncharacterized mechanistically\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified post-translational control of STEAP4 mitochondrial targeting via SIRT3 deacetylation at K404, linking acetylation status to metabolic fate and cuproptosis sensitivity.\",\n      \"evidence\": \"Site-specific K404 mutagenesis, deacetylation assay, mitochondrial fractionation, metabolic flux, HBx mouse and orthotopic HCC models\",\n      \"pmids\": [\"41840161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Acetyltransferase opposing SIRT3 not identified\", \"Generality of K404 regulation beyond HCC unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How STEAP4 partitions its single reductase activity among plasma membrane, endosomal/lysosomal, and mitochondrial pools to produce tissue- and context-specific (protective vs pathogenic) outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified model linking subcellular localization to metal/redox output and downstream pathway selection\", \"Reductase-independent antioxidant effects reported but mechanistically unexplained\", \"Direct in vivo substrate flux at each organelle not measured\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [0, 2, 3, 13, 19, 35]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [6, 7, 8]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [3, 16]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [5, 33, 36]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [16, 37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 10, 12, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 4, 23]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [13, 35, 34]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 13, 35, 26]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [11, 20, 25, 42, 40, 39]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"FAK\", \"AKT\", \"HBx\", \"XIAP\", \"HERP\", \"SIRT3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":8,"faith_pct":87.5}}