{"gene":"STEAP1","run_date":"2026-06-10T07:46:42","timeline":{"discoveries":[{"year":2006,"finding":"STEAP2, STEAP3, and STEAP4 are ferrireductases and cupric reductases that stimulate cellular uptake of both iron and copper in vitro; STEAP1, unlike the other family members, was not demonstrated to have these activities in this study (implicitly negative for STEAP1 ferrireductase/cupric reductase activity in this assay context).","method":"Functional expression studies, cellular iron/copper uptake assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — functional assays replicated across multiple family members with clear positive/negative distinctions, published in high-impact journal with broad citation","pmids":["16609065"],"is_preprint":false},{"year":1999,"finding":"STEAP1 is a six-transmembrane protein localized at cell-cell junctions of the secretory epithelium of the prostate, consistent with a role as a channel or transporter protein at the plasma membrane.","method":"Immunohistochemistry, protein analysis of cancer cell lines, cDNA subtraction cloning","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — protein localization established by IHC and cell surface protein analysis across multiple cell lines, but functional consequence not directly demonstrated","pmids":["10588738"],"is_preprint":false},{"year":2015,"finding":"The STEAP3 transmembrane domain binds a single b-type heme, FAD, and iron; STEAP3 functions as a homodimer using an intrasubunit electron transfer pathway through the single heme rather than an intersubunit pathway. The sequence motifs for FAD and metal binding in the transmembrane domain are conserved in STEAP1 (which lacks the N-terminal oxidoreductase domain), strongly suggesting STEAP1 harbors latent oxidoreductase activity.","method":"Biochemical characterization, mutagenesis, in vitro electron transfer assays, analysis of homodimer vs. domain-swapped dimer","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and multiple biochemical methods; finding for STEAP1 is inferential from sequence conservation but supported by direct experiments on STEAP3 TMD","pmids":["26205815"],"is_preprint":false},{"year":2016,"finding":"Purified rabbit STEAP1 assembles as a homotrimer and forms a heterotrimer when co-expressed with STEAP2. Each STEAP1 protomer binds one b-type heme with histidine axial ligands. In its ferrous state, STEAP1 reduces Fe3+ and Cu2+ complexes and reacts with O2 via an outer-sphere redox mechanism. STEAP1 retains low-affinity FAD binding (KD ~30 µM). Kinetics are biphasic, consistent with heme heterogeneity.","method":"Protein purification at milligram scale, spectroscopic characterization (EPR, UV-vis), stopped-flow kinetics, co-expression experiments","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — first direct biochemical purification and characterization of mammalian STEAP1 with multiple orthogonal biophysical methods in a single rigorous study","pmids":["27792302"],"is_preprint":false},{"year":2020,"finding":"Cryo-EM structure of trimeric human STEAP1 at ~3.0 Å reveals a reductase-like transmembrane conformation. STEAP1 lacks an intracellular NADPH-binding domain and does not exhibit standalone cellular ferric reductase activity. However, STEAP1 promotes iron(III) reduction when fused to the intracellular NADPH-binding domain of STEAP4, demonstrating it can function as a ferric reductase within STEAP heterotrimers. The Fab of antibody mAb120.545 binds the extracellular helices of STEAP1.","method":"Cryo-electron microscopy (3.0 Å resolution), enzymatic assays in human cells using STEAP1-STEAP4 fusion constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with cell-based enzymatic assay and domain-fusion experiment; multiple orthogonal methods in one rigorous study","pmids":["32409586"],"is_preprint":false},{"year":2020,"finding":"The STEAP/NOX ferric reductase superfamily shares a conserved four-helical transmembrane domain with an hourglass shape; within this shared scaffold, STEAP enzymes use FAD (bound to a cytoplasmic F420H2:NADP+-like domain) whereas NOX uses an inner heme, representing a cofactor swap at a topologically equivalent site. The extracellular heme mediates substrate reduction (iron/copper for STEAPs, O2 for NOX).","method":"Structural comparison of cryo-EM structures of NOX and STEAP enzymes","journal":"Accounts of chemical research","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — based on structural analyses; mechanistic conclusions for STEAP1 specifically are inferred from family-level structural comparison rather than direct STEAP1-specific experiment","pmids":["32815713"],"is_preprint":false},{"year":2023,"finding":"STEAP1 can be reduced by exogenous reduced FAD or soluble cytochrome b5 reductase acting as a surrogate oxidoreductase domain, providing the first direct evidence that STEAP1 can support a cross-membrane electron transfer chain. FAD reduced by STEAP2 can be utilized by STEAP1, indicating that FAD is diffusible between STEAP subunits rather than remaining permanently bound to STEAP2. Cryo-EM structure of human STEAP2 in complex with NADP+ and FAD (3.2 Å) confirms cofactor binding similar to STEAP4.","method":"In vitro electron transfer assays with purified proteins, cryo-EM (3.2 Å), FAD transfer experiments between STEAP1 and STEAP2","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution assays plus cryo-EM structure with multiple orthogonal methods; directly establishes STEAP1 electron transfer capability","pmids":["37983176"],"is_preprint":false},{"year":2011,"finding":"STEAP1 knockdown in Ewing tumor cells reduces proliferation, anchorage-independent colony formation, and invasion in vitro, and decreases tumor growth and metastasis in xenografts in vivo. Transcriptome and proteome analyses show STEAP1 expression correlates with oxidative stress responses and elevated reactive oxygen species (ROS), which in turn regulate redox-sensitive and pro-invasive genes. STEAP1 expression is regulated by the EWS/FLI1 fusion oncoprotein.","method":"RNA interference (siRNA/shRNA), in vitro invasion/colony assays, xenograft mouse models, transcriptome and proteome analyses, ROS measurement","journal":"Molecular cancer research : MCR","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function with multiple orthogonal readouts (in vitro and in vivo), replicated across multiple experimental systems","pmids":["22080479"],"is_preprint":false},{"year":2018,"finding":"STEAP1 gene knockdown in LNCaP prostate cancer cells reduces cell viability and proliferation while inducing apoptosis. The pro-survival and anti-apoptotic effects of dihydrotestosterone (DHT) are not dependent on STEAP1, as STEAP1 knockdown effects on apoptosis and proliferation were independent of DHT treatment.","method":"siRNA knockdown, cell viability assays, flow cytometry for apoptosis, DHT treatment","journal":"Medical oncology (Northwood, London, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype; single lab, multiple readouts","pmids":["29464393"],"is_preprint":false},{"year":2008,"finding":"STEAP1 transcription is down-regulated by 17β-estradiol (E2) in rat mammary gland and in MCF-7 breast cancer cells. The mechanism of E2-mediated STEAP1 repression in MCF-7 cells is mediated through membrane-bound ERα (mbERα).","method":"In vivo rat mammary gland E2 treatment, MCF-7 cell hormone treatment, mechanistic studies with membrane-bound ERα","journal":"Endocrine","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct hormone treatment experiments in two models with mechanistic receptor identification; single lab","pmids":["18958632"],"is_preprint":false},{"year":2020,"finding":"STEAP1 promotes metastasis and epithelial-mesenchymal transition (EMT) in lung adenocarcinoma cells via the JAK2/STAT3 signaling pathway. Knockdown of STEAP1 suppressed proliferation, migration, and invasion; these effects were phenocopied by a STAT3 inhibitor (AZD1480), placing STEAP1 upstream of JAK2/STAT3 in this cancer context.","method":"siRNA knockdown, CCK8/EdU/wound healing/transwell assays, Western blot, pharmacological STAT3 inhibition","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — epistasis established by pharmacological inhibitor comparison; single lab, multiple cellular assays","pmids":["32515474"],"is_preprint":false},{"year":2018,"finding":"STEAP1 regulates peritoneal metastasis-related tumorigenesis in gastric cancer cells; RNAi-mediated silencing of STEAP1 inhibits proliferation, migration, invasion, and in vivo tumorigenesis, and increases sensitivity to docetaxel. STEAP1 was identified as the most translationally upregulated gene product in metastatic vs. non-metastatic gastric cancer cells by polysome profiling.","method":"Polysome profiling, siRNA/shRNA knockdown, overexpression plasmid, MTT/migration/invasion assays, xenograft mouse model","journal":"Frontiers in physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays with in vivo validation; single lab","pmids":["30246786"],"is_preprint":false},{"year":2020,"finding":"Phosphorylated eIF4E controls cap-dependent translational upregulation of STEAP1 in gastric cancer cells undergoing peritoneal metastasis. Chemical inhibition or genetic ablation of eIF4E phosphorylation reduces STEAP1 protein levels, placing phospho-eIF4E upstream of STEAP1 in the translational control pathway.","method":"Chemical inhibitors of eIF4E phosphorylation, genetic eIF4E knockout, translational reporter assays, Western blot","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic approaches confirming eIF4E-mediated translational regulation of STEAP1; single lab","pmids":["31949502"],"is_preprint":false},{"year":2020,"finding":"STEAP1 promotes gastric cancer cell proliferation, migration, and invasion via activation of the AKT/FoxO1 pathway and epithelial-mesenchymal transformation (EMT). Both overexpression and knockdown experiments confirmed these effects in vitro and in xenograft mouse models.","method":"Overexpression plasmid, lentiviral shRNA, CCK-8, flow cytometry, colony formation, transwell and wound healing assays, Western blot, subcutaneous and intraperitoneal xenograft","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with pathway analysis (AKT/FoxO1); single lab, multiple orthogonal methods","pmids":["33128353"],"is_preprint":false},{"year":2021,"finding":"NKX2.2 is a transcriptional co-regulator of STEAP1 in Ewing's sarcoma. NKX2.2 binds to two sites in the STEAP1 promoter proximal to EWS/FLI1 binding sites and cooperatively upregulates STEAP1 expression together with EWS/FLI1.","method":"Chromatin immunoprecipitation (ChIP), single-molecule RNA imaging, biochemical and genetic studies, promoter analysis","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly confirms NKX2.2 binding to STEAP1 promoter; single lab with multiple orthogonal methods","pmids":["34073779"],"is_preprint":false},{"year":2022,"finding":"EFEMP1 directly promotes STEAP1 expression in osteosarcoma cells; knockdown of STEAP1 in EFEMP1-overexpressing cells significantly inhibits invasion, EMT, and Wnt/β-catenin and TGF-β/Smad2/3 signaling, placing STEAP1 downstream of EFEMP1 in these pathways. Exogenous EFEMP1 fails to activate these pathways when STEAP1 is knocked down.","method":"Overexpression and knockdown constructs, IHC, RT-qPCR, Western blot, in vitro invasion assays, epistasis experiments","journal":"Journal of bone oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — epistasis established by rescue experiment (EFEMP1 overexpression + STEAP1 knockdown); single lab","pmids":["36388640"],"is_preprint":false},{"year":2023,"finding":"STEAP1 promotes ferroptosis in acute lung injury; inhibition of STEAP1 decreases ROS and MDA levels, increases Nrf2 and GSH levels, and affects the SLC7A11/GPX4 axis, suggesting STEAP1 modulates ferroptosis through this pathway.","method":"siRNA knockdown in HPMECs, LPS-induced ALI model, CLP mouse model, ROS/MDA/GSH/Fe2+ measurements, Western blot","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — loss-of-function in vitro and in vivo with mechanistic pathway readouts; single lab","pmids":["37209327"],"is_preprint":false},{"year":2024,"finding":"METTL14 and IGF2BP2 stabilize STEAP1 mRNA through m6A methylation modification. METTL14 silencing attenuates LPS-induced effects by decreasing STEAP1 expression. This m6A-dependent STEAP1 upregulation aggravates sepsis-induced acute lung injury.","method":"m6A RNA immunoprecipitation, dual-luciferase reporter assay, RNA immunoprecipitation, actinomycin D mRNA stability assay, siRNA knockdown, CLP rat model","journal":"Shock (Augusta, Ga.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — m6A RIP and RNA-IP directly confirm METTL14/IGF2BP2 interaction with STEAP1 mRNA; multiple orthogonal methods; single lab","pmids":["39193903"],"is_preprint":false},{"year":2009,"finding":"STEAP1 depletion by RNAi in human mesenchymal stem cells (MSCs) results in decreased cell adhesion to tissue culture plastic, implicating STEAP1 in cell adhesion in MSCs.","method":"RNAi knockdown in human bone marrow MSCs, cell adhesion assay","journal":"Tissue engineering. Part A","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single functional readout (adhesion) with RNAi; single lab, limited mechanistic follow-up","pmids":["19196137"],"is_preprint":false},{"year":2018,"finding":"A specific anti-STEAP1 scFv antibody binding to STEAP1 epitope significantly inhibits intercellular communication (dye transfer) between prostate cancer cells (PC3 and LNCaP) by ~80-90%, supporting STEAP1's role as a channel or transporter mediating gap junction-like intercellular communication.","method":"Phage library panning for scFv, ELISA, FACS, intercellular dye transfer (gap junction) assay","journal":"Anti-cancer agents in medicinal chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single functional assay with antibody blockade; single lab, indirect mechanistic inference","pmids":["29219059"],"is_preprint":false},{"year":2014,"finding":"STEAP1 expression in prostate cancer is regulated by the androgen receptor (AR) in an AR-dependent manner in CWR22PC cells (in vitro and in vivo), demonstrated by ~66% decline in STEAP1 levels upon AR-targeted treatment monitored by 89Zr-immunoPET.","method":"89Zr-immunoPET imaging, in vitro and in vivo treatment with AR-targeting therapy, ELISA","journal":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct in vivo quantitative imaging plus in vitro validation; single lab, two orthogonal methods","pmids":["25453051"],"is_preprint":false},{"year":2014,"finding":"STEAP1 protein stability and mRNA stability differ between neoplastic (LNCaP) and non-neoplastic (PNT1A) prostate cells. Serum has opposite effects on STEAP1 stability in these two cell types, and in silico analysis predicts post-translational modifications including N-glycosylation, phosphorylation, and O-GlcNAcylation.","method":"mRNA and protein stability experiments, serum treatment, in silico PTM prediction","journal":"Genes & cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — stability assays are indirect; PTM predictions are computational; single lab","pmids":["25053991"],"is_preprint":false},{"year":2021,"finding":"STEAP1 is selectively packaged into small extracellular vesicles (sEVs) from prostate cancer cells irrespective of androgen receptor (AR) status and cellular STEAP1 expression levels, indicating a selective EV-loading mechanism for STEAP1.","method":"Androgen deprivation/AR inhibition in multiple cell lines, Western blot and nanoparticle tracking of sEVs, ex vivo analysis in genetically engineered mice","journal":"Molecular cancer research : MCR","confidence":"Low","confidence_rationale":"Tier 3 / Weak — describes selective EV packaging but mechanism of loading not determined; single lab","pmids":["40287951"],"is_preprint":false},{"year":2018,"finding":"STEAP1 overexpression in breast cancer cells inhibits cellular invasion and migration and reduces EMT marker expression (MMP2, MMP9, MMP13, VIM, CDH2), while increasing CDH1. Knockdown has the opposite effects. STEAP1 had little effect on proliferation in breast cancer cells.","method":"Overexpression and knockdown in breast cancer cell lines, transwell invasion/migration, Western blot for EMT markers","journal":"Clinical breast cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — reciprocal gain/loss-of-function with EMT pathway readout; single lab","pmids":["30253922"],"is_preprint":false},{"year":2026,"finding":"STEAP1 overexpression in oral squamous cell carcinoma (OSCC) cells inhibits proliferation, migration, invasion, and reduces intracellular ROS levels. Mechanistically, STEAP1 overexpression upregulates E-cadherin, downregulates N-cadherin (inhibiting EMT), and decreases β-catenin, Axin2, c-Myc, and p-GSK3β/T-GSK3β ratio (inhibiting Wnt/β-catenin signaling).","method":"Plasmid overexpression in OSCC cell lines, CCK-8, scratch, Transwell assays, ROS measurement, Western blot","journal":"Cancer medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — gain-of-function only, pathway changes by Western blot; single lab, single method per readout","pmids":["42046243"],"is_preprint":false},{"year":2023,"finding":"Proteomic analysis following STEAP1 siRNA knockdown in LNCaP prostate cancer cells identified 526 differentially expressed proteins; downstream pathways affected include endocytosis, apoptosis, and metabolic pathways. STEAP1 silencing specifically induced up-regulation of cathepsin B, intersectin-1, and syntaxin 4, and down-regulation of HRas, PIK3C2A, and DIS3.","method":"siRNA knockdown, label-free LC-MS/MS proteomics (Orbitrap), immunoblotting","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — unbiased proteomics plus immunoblot validation; single lab, two orthogonal methods","pmids":["37315586"],"is_preprint":false}],"current_model":"STEAP1 is a six-transmembrane hemoprotein that assembles as a homotrimer (and heterotrimer with STEAP2/3/4) at the plasma membrane, binds a single b-type heme with histidine axial ligands and low-affinity FAD, and can support cross-membrane electron transfer to reduce Fe3+ and Cu2+ when provided an oxidoreductase domain (either via heterotrimer formation with STEAP2/3/4 or as a domain fusion), explaining its latent ferric/cupric reductase activity despite lacking an intrinsic NADPH-binding domain; in cancer cells, STEAP1 promotes proliferation, invasion, and EMT through ROS-mediated signaling and pathways including JAK2/STAT3, AKT/FoxO1, and Wnt/β-catenin, while its expression is regulated transcriptionally by EWS/FLI1 and NKX2.2, translationally by phospho-eIF4E, and post-transcriptionally by METTL14/IGF2BP2-mediated m6A modification."},"narrative":{"mechanistic_narrative":"STEAP1 is a six-transmembrane plasma-membrane hemoprotein, originally identified at cell-cell junctions of prostate secretory epithelium, that serves as a metalloreductase module within the STEAP family and as a driver of oncogenic phenotypes in multiple cancers [PMID:10588738, PMID:27792302, PMID:22080479]. Biochemically, purified STEAP1 assembles as a homotrimer—and a heterotrimer with STEAP2—with each protomer binding a single b-type heme coordinated by histidine axial ligands, plus low-affinity FAD; in its ferrous state it reduces Fe3+ and Cu2+ and reacts with O2 by an outer-sphere redox mechanism [PMID:27792302]. Unlike STEAP2/3/4, STEAP1 lacks an intracellular NADPH-binding oxidoreductase domain and shows no standalone cellular ferric reductase activity, but the cryo-EM structure reveals a reductase-like transmembrane fold, and STEAP1 gains ferric reductase activity when supplied an oxidoreductase domain—either fused to the STEAP4 NADPH domain, reconstituted with reduced FAD or cytochrome b5 reductase, or supplied diffusible FAD reduced by STEAP2—establishing it as a cross-membrane electron-transfer component dependent on partner subunits [PMID:26205815, PMID:32409586, PMID:37983176]. In cancer, STEAP1 promotes proliferation, invasion, and epithelial-mesenchymal transition, acting through ROS-linked redox signaling and the JAK2/STAT3, AKT/FoxO1, and Wnt/β-catenin pathways, with loss-of-function reducing tumor growth and metastasis in Ewing sarcoma, gastric, lung, and prostate models [PMID:22080479, PMID:32515474, PMID:33128353, PMID:42046243]. Its expression is controlled at multiple levels: transcriptionally by the EWS/FLI1 fusion oncoprotein cooperating with NKX2.2, and by the androgen receptor in prostate cancer; translationally by phospho-eIF4E; and post-transcriptionally by METTL14/IGF2BP2-mediated m6A mRNA stabilization [PMID:22080479, PMID:34073779, PMID:25453051, PMID:31949502, PMID:39193903]. Notably, STEAP1 acts as a tumor suppressor in some contexts, with overexpression in breast and oral squamous carcinoma inhibiting invasion and EMT [PMID:30253922, PMID:42046243].","teleology":[{"year":1999,"claim":"Established STEAP1's existence and subcellular setting—a six-transmembrane protein at prostate epithelial cell-cell junctions—framing the initial hypothesis that it is a channel or transporter.","evidence":"cDNA subtraction cloning, IHC and cell-surface protein analysis across cancer cell lines","pmids":["10588738"],"confidence":"Medium","gaps":["No transport or enzymatic activity demonstrated","Functional role of junctional localization unresolved"]},{"year":2006,"claim":"Demonstrated that STEAP2/3/4 are ferri/cupric reductases stimulating iron and copper uptake, while STEAP1 was negative in the same assay—defining the central puzzle of STEAP1's apparent lack of intrinsic reductase activity.","evidence":"Functional expression and cellular iron/copper uptake assays","pmids":["16609065"],"confidence":"High","gaps":["Did not test whether STEAP1 is active with a supplied oxidoreductase partner","No structural basis offered"]},{"year":2015,"claim":"Showed STEAP3 binds heme, FAD, and iron and transfers electrons through a single heme, with FAD/metal-binding motifs conserved in STEAP1—predicting latent oxidoreductase capacity for the domainless STEAP1.","evidence":"Biochemical reconstitution, mutagenesis, in vitro electron transfer on STEAP3 TMD","pmids":["26205815"],"confidence":"High","gaps":["STEAP1 activity inferred from sequence conservation, not directly assayed","Source of electrons for STEAP1 unaddressed"]},{"year":2016,"claim":"Provided the first direct biochemical proof that mammalian STEAP1 is a homotrimeric hemoprotein that reduces Fe3+/Cu2+ in its ferrous state and forms heterotrimers with STEAP2, establishing the cofactor architecture.","evidence":"Milligram-scale purification of rabbit STEAP1, EPR/UV-vis spectroscopy, stopped-flow kinetics, co-expression","pmids":["27792302"],"confidence":"High","gaps":["Physiological electron donor in cells not identified","Did not resolve standalone vs. partner-dependent activity in cellular context"]},{"year":2020,"claim":"Resolved the cryo-EM structure of human STEAP1 and proved that, lacking an NADPH domain, it has no standalone ferric reductase activity but becomes active when fused to the STEAP4 NADPH domain—defining it as a partner-dependent reductase.","evidence":"Cryo-EM at 3.0 Å, cell-based enzymatic assays with STEAP1-STEAP4 fusion constructs","pmids":["32409586"],"confidence":"High","gaps":["Whether native heterotrimers form and function in vivo not directly shown","Electron donor in physiological setting unresolved"]},{"year":2023,"claim":"Directly demonstrated STEAP1 can support a cross-membrane electron transfer chain using surrogate oxidoreductases and showed FAD is diffusible between STEAP subunits, mechanistically completing the partner-dependent reductase model.","evidence":"In vitro electron transfer assays with purified proteins, FAD-transfer experiments, cryo-EM of STEAP2 (3.2 Å)","pmids":["37983176"],"confidence":"High","gaps":["In vivo relevance of FAD diffusion between subunits not established","Endogenous oxidoreductase partner not identified in cells"]},{"year":2011,"claim":"Connected STEAP1 to tumor biology by showing knockdown reduces Ewing tumor growth, invasion, and metastasis, with effects linked to ROS and EWS/FLI1-driven expression—establishing a redox-coupled oncogenic role.","evidence":"RNAi, in vitro invasion/colony assays, xenografts, transcriptome/proteome, ROS measurement","pmids":["22080479"],"confidence":"High","gaps":["Direct link between reductase activity and ROS generation not demonstrated","Downstream pro-invasive effectors only partly defined"]},{"year":2020,"claim":"Defined cancer-context signaling routes for STEAP1, placing it upstream of JAK2/STAT3 in lung adenocarcinoma and of AKT/FoxO1 in gastric cancer to drive proliferation, migration, and EMT.","evidence":"siRNA/overexpression, pharmacological STAT3 inhibition (epistasis), migration/invasion assays, xenografts, Western blot","pmids":["32515474","33128353"],"confidence":"Medium","gaps":["Mechanism linking STEAP1 to pathway activation unclear","Single-lab findings per cancer type"]},{"year":2021,"claim":"Mapped layered regulation of STEAP1 expression—NKX2.2 cooperating with EWS/FLI1 transcriptionally, phospho-eIF4E translationally, and androgen receptor in prostate cancer—explaining its context-specific overexpression.","evidence":"ChIP and promoter analysis, eIF4E inhibition/knockout, AR-targeted treatment with 89Zr-immunoPET","pmids":["34073779","31949502","25453051"],"confidence":"Medium","gaps":["Relative contribution of each regulatory layer per tissue unknown","Whether regulation feeds back to reductase function unaddressed"]},{"year":2024,"claim":"Extended STEAP1 regulation to m6A epitranscriptomics, showing METTL14/IGF2BP2 stabilize STEAP1 mRNA and that this aggravates sepsis-induced acute lung injury via ferroptosis pathways.","evidence":"m6A-RIP, RNA-IP, mRNA stability assay, dual-luciferase reporter, siRNA, CLP rodent models","pmids":["39193903","37209327"],"confidence":"Medium","gaps":["Mechanism by which STEAP1 modulates SLC7A11/GPX4 axis not resolved","Link between reductase activity and ferroptosis not directly tested"]},{"year":2026,"claim":"Identified a context-dependent tumor-suppressive role, with STEAP1 overexpression inhibiting invasion, EMT, and Wnt/β-catenin signaling in breast and oral squamous carcinoma—contrasting its oncogenic role elsewhere.","evidence":"Reciprocal overexpression/knockdown, transwell invasion, EMT marker and Wnt pathway Western blots, ROS measurement","pmids":["30253922","42046243"],"confidence":"Low","gaps":["Gain-of-function only in OSCC; single method per readout","Mechanistic basis for opposite roles across tissues unexplained"]},{"year":null,"claim":"The identity of STEAP1's endogenous oxidoreductase partner in living cells, and the causal link between its metalloreductase/ROS activity and its divergent oncogenic versus tumor-suppressive signaling outputs, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No identified physiological electron donor in native cellular context","No mechanism reconciling pro-tumor and anti-tumor phenotypes across tissues","Direct test linking reductase catalysis to downstream signaling absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[3,4,6]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[3,6]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,3]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[4,6]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,13]}],"complexes":["STEAP1 homotrimer","STEAP1/STEAP2 heterotrimer"],"partners":["STEAP2","STEAP4","METTL14","IGF2BP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UHE8","full_name":"STEAP1 protein","aliases":["Six-transmembrane epithelial antigen of prostate 1"],"length_aa":339,"mass_kda":39.9,"function":"Does not function as a metalloreductase due to the absence of binding sites for the electron-donating substrate NADPH. Promotes Fe(3+) reduction when fused to the NADPH-binding domain of STEAP4","subcellular_location":"Endosome membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9UHE8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STEAP1","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1090,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/STEAP1","total_profiled":1310},"omim":[{"mim_id":"604415","title":"STEAP FAMILY MEMBER 1; STEAP1","url":"https://www.omim.org/entry/604415"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"prostate","ntpm":78.6}],"url":"https://www.proteinatlas.org/search/STEAP1"},"hgnc":{"alias_symbol":["PRSS24"],"prev_symbol":["STEAP"]},"alphafold":{"accession":"Q9UHE8","domains":[{"cath_id":"-","chopping":"70-339","consensus_level":"high","plddt":95.4764,"start":70,"end":339}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHE8","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHE8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UHE8-F1-predicted_aligned_error_v6.png","plddt_mean":84.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STEAP1","jax_strain_url":"https://www.jax.org/strain/search?query=STEAP1"},"sequence":{"accession":"Q9UHE8","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UHE8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UHE8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UHE8"}},"corpus_meta":[{"pmid":"16609065","id":"PMC_16609065","title":"The Steap proteins are metalloreductases.","date":"2006","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16609065","citation_count":543,"is_preprint":false},{"pmid":"10588738","id":"PMC_10588738","title":"STEAP: a prostate-specific cell-surface antigen highly expressed in human prostate tumors.","date":"1999","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10588738","citation_count":295,"is_preprint":false},{"pmid":"22522456","id":"PMC_22522456","title":"STEAP proteins: from structure to applications in cancer therapy.","date":"2012","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/22522456","citation_count":154,"is_preprint":false},{"pmid":"21913715","id":"PMC_21913715","title":"Impact of drug conjugation on pharmacokinetics and tissue distribution of anti-STEAP1 antibody-drug conjugates in rats.","date":"2011","source":"Bioconjugate chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21913715","citation_count":153,"is_preprint":false},{"pmid":"17695374","id":"PMC_17695374","title":"Steap proteins: implications for iron and copper metabolism.","date":"2007","source":"Nutrition reviews","url":"https://pubmed.ncbi.nlm.nih.gov/17695374","citation_count":123,"is_preprint":false},{"pmid":"37041154","id":"PMC_37041154","title":"Targeting advanced prostate cancer with STEAP1 chimeric antigen receptor T cell and tumor-localized IL-12 immunotherapy.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37041154","citation_count":116,"is_preprint":false},{"pmid":"22080479","id":"PMC_22080479","title":"STEAP1 is associated with the invasive and oxidative stress phenotype of Ewing tumors.","date":"2011","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/22080479","citation_count":108,"is_preprint":false},{"pmid":"37861461","id":"PMC_37861461","title":"Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study.","date":"2024","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37861461","citation_count":88,"is_preprint":false},{"pmid":"22804687","id":"PMC_22804687","title":"The STEAP protein family: versatile oxidoreductases and targets for cancer immunotherapy with overlapping and distinct cellular functions.","date":"2012","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/22804687","citation_count":79,"is_preprint":false},{"pmid":"23142226","id":"PMC_23142226","title":"STEAP1 is overexpressed in cancers: a promising therapeutic target.","date":"2012","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/23142226","citation_count":67,"is_preprint":false},{"pmid":"24239460","id":"PMC_24239460","title":"STEAP1 is overexpressed in prostate cancer and prostatic intraepithelial neoplasia lesions, and it is positively associated with Gleason score.","date":"2013","source":"Urologic oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24239460","citation_count":57,"is_preprint":false},{"pmid":"16622681","id":"PMC_16622681","title":"STEAP, a prostate tumor antigen, is a target of human CD8+ T cells.","date":"2006","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/16622681","citation_count":56,"is_preprint":false},{"pmid":"26205815","id":"PMC_26205815","title":"Characterization of a single b-type heme, FAD, and metal binding sites in the transmembrane domain of six-transmembrane epithelial antigen of the prostate (STEAP) family proteins.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26205815","citation_count":52,"is_preprint":false},{"pmid":"36011027","id":"PMC_36011027","title":"STEAP1-4 (Six-Transmembrane Epithelial Antigen of the Prostate 1-4) and Their Clinical Implications for Prostate Cancer.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36011027","citation_count":47,"is_preprint":false},{"pmid":"24025158","id":"PMC_24025158","title":"STEAP1 protein overexpression is an independent marker for biochemical recurrence in prostate carcinoma.","date":"2013","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/24025158","citation_count":45,"is_preprint":false},{"pmid":"22317770","id":"PMC_22317770","title":"High STEAP1 expression is associated with improved outcome of Ewing's sarcoma patients.","date":"2012","source":"Annals of oncology : official journal of the European Society for Medical Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/22317770","citation_count":45,"is_preprint":false},{"pmid":"37861452","id":"PMC_37861452","title":"AMG 509 (Xaluritamig), an Anti-STEAP1 XmAb 2+1 T-cell Redirecting Immune Therapy with Avidity-Dependent Activity against Prostate Cancer.","date":"2024","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/37861452","citation_count":44,"is_preprint":false},{"pmid":"29464393","id":"PMC_29464393","title":"Knockdown of STEAP1 inhibits cell growth and induces apoptosis in LNCaP prostate cancer cells counteracting the effect of androgens.","date":"2018","source":"Medical oncology (Northwood, London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/29464393","citation_count":43,"is_preprint":false},{"pmid":"21182993","id":"PMC_21182993","title":"Immunization with recombinant DNA and modified vaccinia virus Ankara (MVA) vectors delivering PSCA and STEAP1 antigens inhibits prostate cancer progression.","date":"2010","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/21182993","citation_count":40,"is_preprint":false},{"pmid":"32409586","id":"PMC_32409586","title":"Cryo-electron microscopy structure and potential enzymatic function of human six-transmembrane epithelial antigen of the prostate 1 (STEAP1).","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32409586","citation_count":39,"is_preprint":false},{"pmid":"28460619","id":"PMC_28460619","title":"Targeting STEAP1 Protein in Human Cancer: Current Trends and Future Challenges.","date":"2018","source":"Current cancer drug targets","url":"https://pubmed.ncbi.nlm.nih.gov/28460619","citation_count":38,"is_preprint":false},{"pmid":"27792302","id":"PMC_27792302","title":"Six-Transmembrane Epithelial Antigen of Prostate 1 (STEAP1) Has a Single b Heme and Is Capable of Reducing Metal Ion Complexes and Oxygen.","date":"2016","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/27792302","citation_count":37,"is_preprint":false},{"pmid":"34497115","id":"PMC_34497115","title":"Novel potent anti-STEAP1 bispecific antibody to redirect T cells for cancer immunotherapy.","date":"2021","source":"Journal for immunotherapy of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/34497115","citation_count":36,"is_preprint":false},{"pmid":"18958632","id":"PMC_18958632","title":"STEAP1 is over-expressed in breast cancer and down-regulated by 17beta-estradiol in MCF-7 cells and in the rat mammary gland.","date":"2008","source":"Endocrine","url":"https://pubmed.ncbi.nlm.nih.gov/18958632","citation_count":35,"is_preprint":false},{"pmid":"33589770","id":"PMC_33589770","title":"Clinical significance of STEAP1 extracellular vesicles in prostate cancer.","date":"2021","source":"Prostate cancer and prostatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/33589770","citation_count":33,"is_preprint":false},{"pmid":"32515474","id":"PMC_32515474","title":"STEAP1 facilitates metastasis and epithelial-mesenchymal transition of lung adenocarcinoma via the JAK2/STAT3 signaling pathway.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/32515474","citation_count":31,"is_preprint":false},{"pmid":"30246786","id":"PMC_30246786","title":"STEAP1 Regulates Tumorigenesis and Chemoresistance During Peritoneal Metastasis of Gastric Cancer.","date":"2018","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30246786","citation_count":27,"is_preprint":false},{"pmid":"27029064","id":"PMC_27029064","title":"ImmunoPET helps predicting the efficacy of antibody-drug conjugates targeting TENB2 and STEAP1.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/27029064","citation_count":27,"is_preprint":false},{"pmid":"32610710","id":"PMC_32610710","title":"MHC Class I-Restricted TCR-Transgenic CD4+ T Cells Against STEAP1 Mediate Local Tumor Control of Ewing Sarcoma In Vivo.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/32610710","citation_count":26,"is_preprint":false},{"pmid":"33128353","id":"PMC_33128353","title":"A research of STEAP1 regulated gastric cancer cell proliferation, migration and invasion in vitro and in vivos.","date":"2020","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33128353","citation_count":25,"is_preprint":false},{"pmid":"27471654","id":"PMC_27471654","title":"Transgenic antigen-specific, HLA-A*02:01-allo-restricted cytotoxic T cells recognize tumor-associated target antigen STEAP1 with high specificity.","date":"2016","source":"Oncoimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/27471654","citation_count":25,"is_preprint":false},{"pmid":"25453051","id":"PMC_25453051","title":"Annotating STEAP1 regulation in prostate cancer with 89Zr immuno-PET.","date":"2014","source":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25453051","citation_count":24,"is_preprint":false},{"pmid":"25053991","id":"PMC_25053991","title":"Expression of STEAP1 and STEAP1B in prostate cell lines, and the putative regulation of STEAP1 by post-transcriptional and post-translational mechanisms.","date":"2014","source":"Genes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/25053991","citation_count":24,"is_preprint":false},{"pmid":"35860008","id":"PMC_35860008","title":"Development of STEAP1 targeting chimeric antigen receptor for adoptive cell therapy against cancer.","date":"2022","source":"Molecular therapy oncolytics","url":"https://pubmed.ncbi.nlm.nih.gov/35860008","citation_count":23,"is_preprint":false},{"pmid":"30253922","id":"PMC_30253922","title":"STEAP1 Inhibits Breast Cancer Metastasis and Is Associated With Epithelial-Mesenchymal Transition Procession.","date":"2018","source":"Clinical breast cancer","url":"https://pubmed.ncbi.nlm.nih.gov/30253922","citation_count":19,"is_preprint":false},{"pmid":"37209327","id":"PMC_37209327","title":"Inhibition of STEAP1 ameliorates inflammation and ferroptosis of acute lung injury caused by sepsis in LPS-induced human pulmonary microvascular endothelial cells.","date":"2023","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/37209327","citation_count":19,"is_preprint":false},{"pmid":"34649092","id":"PMC_34649092","title":"Predictive potential of STEAP family for survival, immune microenvironment and therapy response in glioma.","date":"2021","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/34649092","citation_count":18,"is_preprint":false},{"pmid":"29219059","id":"PMC_29219059","title":"Inhibition of Intercellular Communication between Prostate Cancer Cells by A Specific Anti-STEAP-1 Single Chain Antibody.","date":"2018","source":"Anti-cancer agents in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29219059","citation_count":16,"is_preprint":false},{"pmid":"40185436","id":"PMC_40185436","title":"STEAP Proteins: Roles in disease biology and potential for therapeutic intervention.","date":"2025","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/40185436","citation_count":15,"is_preprint":false},{"pmid":"26715028","id":"PMC_26715028","title":"The STEAP1(262-270) peptide encapsulated into PLGA microspheres elicits strong cytotoxic T cell immunity in HLA-A*0201 transgenic mice--A new approach to immunotherapy against prostate carcinoma.","date":"2015","source":"The Prostate","url":"https://pubmed.ncbi.nlm.nih.gov/26715028","citation_count":15,"is_preprint":false},{"pmid":"32815713","id":"PMC_32815713","title":"An Elegant Four-Helical Fold in NOX and STEAP Enzymes Facilitates Electron Transport across Biomembranes-Similar Vehicle, Different Destination.","date":"2020","source":"Accounts of chemical research","url":"https://pubmed.ncbi.nlm.nih.gov/32815713","citation_count":14,"is_preprint":false},{"pmid":"19196137","id":"PMC_19196137","title":"Six-transmembrane epithelial antigen of the prostate (STEAP1 and STEAP2)-differentially expressed by murine and human mesenchymal stem cells.","date":"2009","source":"Tissue engineering. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/19196137","citation_count":14,"is_preprint":false},{"pmid":"36388640","id":"PMC_36388640","title":"EFEMP1 binds to STEAP1 to promote osteosarcoma proliferation and invasion via the Wnt/β-catenin and TGF-β/Smad2/3 signal pathways.","date":"2022","source":"Journal of bone oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36388640","citation_count":13,"is_preprint":false},{"pmid":"30841425","id":"PMC_30841425","title":"Inhibition of mouse RM-1 prostate cancer and B16F10 melanoma by the fusion protein of HSP65 & STEAP1 186-193.","date":"2019","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/30841425","citation_count":13,"is_preprint":false},{"pmid":"31949502","id":"PMC_31949502","title":"EIF4E regulates STEAP1 expression in peritoneal metastasis.","date":"2020","source":"Journal of Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/31949502","citation_count":11,"is_preprint":false},{"pmid":"34358202","id":"PMC_34358202","title":"Fusion Protein Vaccine Based on Ag85B and STEAP1 Induces a Protective Immune Response against Prostate Cancer.","date":"2021","source":"Vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/34358202","citation_count":11,"is_preprint":false},{"pmid":"37192590","id":"PMC_37192590","title":"Development of a novel electrochemical biosensor based on plastic antibodies for detection of STEAP1 biomarker in cancer.","date":"2023","source":"Bioelectrochemistry (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/37192590","citation_count":11,"is_preprint":false},{"pmid":"41125870","id":"PMC_41125870","title":"Collagen-binding IL-12-armoured STEAP1 CAR-T cells reduce toxicity and treat prostate cancer in mouse models.","date":"2025","source":"Nature biomedical engineering","url":"https://pubmed.ncbi.nlm.nih.gov/41125870","citation_count":10,"is_preprint":false},{"pmid":"34073779","id":"PMC_34073779","title":"Identification of a New Transcriptional Co-Regulator of STEAP1 in Ewing's Sarcoma.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34073779","citation_count":10,"is_preprint":false},{"pmid":"37909017","id":"PMC_37909017","title":"Targeting STEAP1 as an anticancer strategy.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37909017","citation_count":7,"is_preprint":false},{"pmid":"37983176","id":"PMC_37983176","title":"Mechanism of stepwise electron transfer in six-transmembrane epithelial antigen of the prostate (STEAP) 1 and 2.","date":"2023","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/37983176","citation_count":7,"is_preprint":false},{"pmid":"30027616","id":"PMC_30027616","title":"Six-Transmembrane Epithelial Antigen of the Prostate-1 (STEAP-1)-Targeted Ultrasound Imaging Microbubble Improves Detection of Prostate Cancer In Vivo.","date":"2018","source":"Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30027616","citation_count":7,"is_preprint":false},{"pmid":"34576175","id":"PMC_34576175","title":"Enhanced Stability of Detergent-Free Human Native STEAP1 Protein from Neoplastic Prostate Cancer Cells upon an Innovative Isolation Procedure.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34576175","citation_count":7,"is_preprint":false},{"pmid":"40299363","id":"PMC_40299363","title":"The Role of STEAP1 in Prostate Cancer: Implications for Diagnosis and Therapeutic Strategies.","date":"2025","source":"Biomedicines","url":"https://pubmed.ncbi.nlm.nih.gov/40299363","citation_count":6,"is_preprint":false},{"pmid":"40527692","id":"PMC_40527692","title":"STEAP1: a promising target in prostate cancer therapy.","date":"2025","source":"Trends in cancer","url":"https://pubmed.ncbi.nlm.nih.gov/40527692","citation_count":5,"is_preprint":false},{"pmid":"37315586","id":"PMC_37315586","title":"Proteomic analysis of STEAP1 knockdown in human LNCaP prostate cancer cells.","date":"2023","source":"Biochimica et biophysica acta. Molecular cell research","url":"https://pubmed.ncbi.nlm.nih.gov/37315586","citation_count":5,"is_preprint":false},{"pmid":"37047621","id":"PMC_37047621","title":"STEAP1 Knockdown Decreases the Sensitivity of Prostate Cancer Cells to Paclitaxel, Docetaxel and Cabazitaxel.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37047621","citation_count":5,"is_preprint":false},{"pmid":"36660947","id":"PMC_36660947","title":"STEAP1 regulation and its influence modulating the response of LNCaP prostate cancer cells to bicalutamide, enzalutamide and apalutamide.","date":"2023","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/36660947","citation_count":5,"is_preprint":false},{"pmid":"38203757","id":"PMC_38203757","title":"Comparative Evaluation of STEAP1 Targeting Chimeric Antigen Receptors with Different Costimulatory Domains and Spacers.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38203757","citation_count":5,"is_preprint":false},{"pmid":"40287951","id":"PMC_40287951","title":"Exploring STEAP1 Expression in Prostate Cancer Cells in Response to Androgen Deprivation and in Small Extracellular Vesicles.","date":"2025","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/40287951","citation_count":4,"is_preprint":false},{"pmid":"39193903","id":"PMC_39193903","title":"METTL14/IGF2BP2-MEDIATED M6A MODIFICATION OF STEAP1 AGGRAVATES ACUTE LUNG INJURY INDUCED BY SEPSIS.","date":"2024","source":"Shock (Augusta, Ga.)","url":"https://pubmed.ncbi.nlm.nih.gov/39193903","citation_count":4,"is_preprint":false},{"pmid":"34059939","id":"PMC_34059939","title":"Impact of glycerol feeding profiles on STEAP1 biosynthesis by Komagataella pastoris using a methanol-inducible promoter.","date":"2021","source":"Applied microbiology and biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/34059939","citation_count":3,"is_preprint":false},{"pmid":"40304166","id":"PMC_40304166","title":"A pH/STEAP Cascade-Responsive Nanomedicine with Self-Supplied Peroxide for Precise Chemodynamic Therapy.","date":"2025","source":"Advanced healthcare materials","url":"https://pubmed.ncbi.nlm.nih.gov/40304166","citation_count":2,"is_preprint":false},{"pmid":"40358178","id":"PMC_40358178","title":"The Six-Transmembrane Epithelial Antigen of the Prostate (STEAP) 3 Regulates the Myogenic Differentiation of Yunan Black Pig Muscle Satellite Cells (MuSCs) In Vitro via Iron Homeostasis and the PI3K/AKT Pathway.","date":"2025","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/40358178","citation_count":1,"is_preprint":false},{"pmid":"41500147","id":"PMC_41500147","title":"Diversity and similarity of metallothionein and STEAP gene regulation by heavy metals in human colorectal cells.","date":"2026","source":"Legal medicine (Tokyo, Japan)","url":"https://pubmed.ncbi.nlm.nih.gov/41500147","citation_count":1,"is_preprint":false},{"pmid":"41415362","id":"PMC_41415362","title":"Armoring STEAP1 CAR T cells with IL-18 potentiates antitumor activity in Ewing sarcoma.","date":"2025","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/41415362","citation_count":0,"is_preprint":false},{"pmid":"41131283","id":"PMC_41131283","title":"STEAP1-targeted strategies in advanced prostate cancer: a review on therapeutic and diagnostic implications.","date":"2025","source":"Prostate cancer and prostatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/41131283","citation_count":0,"is_preprint":false},{"pmid":"42046243","id":"PMC_42046243","title":"STEAP1 Suppresses Oral Squamous Cell Carcinoma by Targeting Wnt/β-Catenin Signalling and EMT.","date":"2026","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42046243","citation_count":0,"is_preprint":false},{"pmid":"42189191","id":"PMC_42189191","title":"Integrative Surface Antigen Profiling of KLK2 and STEAP1 in Advanced Prostate Cancer.","date":"2026","source":"Molecular cancer research : MCR","url":"https://pubmed.ncbi.nlm.nih.gov/42189191","citation_count":0,"is_preprint":false},{"pmid":"41668284","id":"PMC_41668284","title":"Characterization of an anti-STEAP1 T-cell dependent bispecific antibody for the treatment of prostate cancer and associated toxicity in cynomolgus monkeys.","date":"2026","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/41668284","citation_count":0,"is_preprint":false},{"pmid":"41737989","id":"PMC_41737989","title":"Preclinical Assessment of HLA-A*02:01-Restricted PSMA and STEAP1 Epitopes for Peptide-Based Immunotherapy in Prostate Cancer.","date":"2026","source":"Drug design, development and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/41737989","citation_count":0,"is_preprint":false},{"pmid":"41900874","id":"PMC_41900874","title":"Mechanistic Modulation of Lipopolysaccharide-Induced Hepatic Injury by Chitosan-Coated Selenium Nanoparticles: Targeting the STEAP-3/TLR-4 and IL-17/TRAF-6/HSP-90 Axes.","date":"2026","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/41900874","citation_count":0,"is_preprint":false},{"pmid":"41868236","id":"PMC_41868236","title":"Immunoinformatics-driven multi-epitope vaccine design targeting PSMA, STEAP1, and B7H3 for prostate cancer.","date":"2026","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41868236","citation_count":0,"is_preprint":false},{"pmid":"42078873","id":"PMC_42078873","title":"Development of a STEAP1-Targeted Prostate Cancer Specific Antibody Drug Conjugate Platform with Immunostimulatory Properties.","date":"2026","source":"Research square","url":"https://pubmed.ncbi.nlm.nih.gov/42078873","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.05.674562","title":"Genotoxic antibody-drug conjugates combined with Bcl-xL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer","date":"2025-09-11","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.05.674562","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.19.644145","title":"<i>Collagen-binding IL-12 expressing</i>  STEAP1 CAR-T cells reduce toxicity and eradicate mouse prostate cancer in combination with checkpoint inhibitors","date":"2025-03-19","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.19.644145","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":40229,"output_tokens":6505,"usd":0.109131,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15489,"output_tokens":4018,"usd":0.088947,"stage2_stop_reason":"end_turn"},"total_usd":0.198078,"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\": 2006,\n      \"finding\": \"STEAP2, STEAP3, and STEAP4 are ferrireductases and cupric reductases that stimulate cellular uptake of both iron and copper in vitro; STEAP1, unlike the other family members, was not demonstrated to have these activities in this study (implicitly negative for STEAP1 ferrireductase/cupric reductase activity in this assay context).\",\n      \"method\": \"Functional expression studies, cellular iron/copper uptake assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — functional assays replicated across multiple family members with clear positive/negative distinctions, published in high-impact journal with broad citation\",\n      \"pmids\": [\"16609065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"STEAP1 is a six-transmembrane protein localized at cell-cell junctions of the secretory epithelium of the prostate, consistent with a role as a channel or transporter protein at the plasma membrane.\",\n      \"method\": \"Immunohistochemistry, protein analysis of cancer cell lines, cDNA subtraction cloning\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — protein localization established by IHC and cell surface protein analysis across multiple cell lines, but functional consequence not directly demonstrated\",\n      \"pmids\": [\"10588738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The STEAP3 transmembrane domain binds a single b-type heme, FAD, and iron; STEAP3 functions as a homodimer using an intrasubunit electron transfer pathway through the single heme rather than an intersubunit pathway. The sequence motifs for FAD and metal binding in the transmembrane domain are conserved in STEAP1 (which lacks the N-terminal oxidoreductase domain), strongly suggesting STEAP1 harbors latent oxidoreductase activity.\",\n      \"method\": \"Biochemical characterization, mutagenesis, in vitro electron transfer assays, analysis of homodimer vs. domain-swapped dimer\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with mutagenesis and multiple biochemical methods; finding for STEAP1 is inferential from sequence conservation but supported by direct experiments on STEAP3 TMD\",\n      \"pmids\": [\"26205815\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Purified rabbit STEAP1 assembles as a homotrimer and forms a heterotrimer when co-expressed with STEAP2. Each STEAP1 protomer binds one b-type heme with histidine axial ligands. In its ferrous state, STEAP1 reduces Fe3+ and Cu2+ complexes and reacts with O2 via an outer-sphere redox mechanism. STEAP1 retains low-affinity FAD binding (KD ~30 µM). Kinetics are biphasic, consistent with heme heterogeneity.\",\n      \"method\": \"Protein purification at milligram scale, spectroscopic characterization (EPR, UV-vis), stopped-flow kinetics, co-expression experiments\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — first direct biochemical purification and characterization of mammalian STEAP1 with multiple orthogonal biophysical methods in a single rigorous study\",\n      \"pmids\": [\"27792302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cryo-EM structure of trimeric human STEAP1 at ~3.0 Å reveals a reductase-like transmembrane conformation. STEAP1 lacks an intracellular NADPH-binding domain and does not exhibit standalone cellular ferric reductase activity. However, STEAP1 promotes iron(III) reduction when fused to the intracellular NADPH-binding domain of STEAP4, demonstrating it can function as a ferric reductase within STEAP heterotrimers. The Fab of antibody mAb120.545 binds the extracellular helices of STEAP1.\",\n      \"method\": \"Cryo-electron microscopy (3.0 Å resolution), enzymatic assays in human cells using STEAP1-STEAP4 fusion constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with cell-based enzymatic assay and domain-fusion experiment; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"32409586\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The STEAP/NOX ferric reductase superfamily shares a conserved four-helical transmembrane domain with an hourglass shape; within this shared scaffold, STEAP enzymes use FAD (bound to a cytoplasmic F420H2:NADP+-like domain) whereas NOX uses an inner heme, representing a cofactor swap at a topologically equivalent site. The extracellular heme mediates substrate reduction (iron/copper for STEAPs, O2 for NOX).\",\n      \"method\": \"Structural comparison of cryo-EM structures of NOX and STEAP enzymes\",\n      \"journal\": \"Accounts of chemical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — based on structural analyses; mechanistic conclusions for STEAP1 specifically are inferred from family-level structural comparison rather than direct STEAP1-specific experiment\",\n      \"pmids\": [\"32815713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STEAP1 can be reduced by exogenous reduced FAD or soluble cytochrome b5 reductase acting as a surrogate oxidoreductase domain, providing the first direct evidence that STEAP1 can support a cross-membrane electron transfer chain. FAD reduced by STEAP2 can be utilized by STEAP1, indicating that FAD is diffusible between STEAP subunits rather than remaining permanently bound to STEAP2. Cryo-EM structure of human STEAP2 in complex with NADP+ and FAD (3.2 Å) confirms cofactor binding similar to STEAP4.\",\n      \"method\": \"In vitro electron transfer assays with purified proteins, cryo-EM (3.2 Å), FAD transfer experiments between STEAP1 and STEAP2\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution assays plus cryo-EM structure with multiple orthogonal methods; directly establishes STEAP1 electron transfer capability\",\n      \"pmids\": [\"37983176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"STEAP1 knockdown in Ewing tumor cells reduces proliferation, anchorage-independent colony formation, and invasion in vitro, and decreases tumor growth and metastasis in xenografts in vivo. Transcriptome and proteome analyses show STEAP1 expression correlates with oxidative stress responses and elevated reactive oxygen species (ROS), which in turn regulate redox-sensitive and pro-invasive genes. STEAP1 expression is regulated by the EWS/FLI1 fusion oncoprotein.\",\n      \"method\": \"RNA interference (siRNA/shRNA), in vitro invasion/colony assays, xenograft mouse models, transcriptome and proteome analyses, ROS measurement\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function with multiple orthogonal readouts (in vitro and in vivo), replicated across multiple experimental systems\",\n      \"pmids\": [\"22080479\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"STEAP1 gene knockdown in LNCaP prostate cancer cells reduces cell viability and proliferation while inducing apoptosis. The pro-survival and anti-apoptotic effects of dihydrotestosterone (DHT) are not dependent on STEAP1, as STEAP1 knockdown effects on apoptosis and proliferation were independent of DHT treatment.\",\n      \"method\": \"siRNA knockdown, cell viability assays, flow cytometry for apoptosis, DHT treatment\",\n      \"journal\": \"Medical oncology (Northwood, London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with defined cellular phenotype; single lab, multiple readouts\",\n      \"pmids\": [\"29464393\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"STEAP1 transcription is down-regulated by 17β-estradiol (E2) in rat mammary gland and in MCF-7 breast cancer cells. The mechanism of E2-mediated STEAP1 repression in MCF-7 cells is mediated through membrane-bound ERα (mbERα).\",\n      \"method\": \"In vivo rat mammary gland E2 treatment, MCF-7 cell hormone treatment, mechanistic studies with membrane-bound ERα\",\n      \"journal\": \"Endocrine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct hormone treatment experiments in two models with mechanistic receptor identification; single lab\",\n      \"pmids\": [\"18958632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STEAP1 promotes metastasis and epithelial-mesenchymal transition (EMT) in lung adenocarcinoma cells via the JAK2/STAT3 signaling pathway. Knockdown of STEAP1 suppressed proliferation, migration, and invasion; these effects were phenocopied by a STAT3 inhibitor (AZD1480), placing STEAP1 upstream of JAK2/STAT3 in this cancer context.\",\n      \"method\": \"siRNA knockdown, CCK8/EdU/wound healing/transwell assays, Western blot, pharmacological STAT3 inhibition\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — epistasis established by pharmacological inhibitor comparison; single lab, multiple cellular assays\",\n      \"pmids\": [\"32515474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"STEAP1 regulates peritoneal metastasis-related tumorigenesis in gastric cancer cells; RNAi-mediated silencing of STEAP1 inhibits proliferation, migration, invasion, and in vivo tumorigenesis, and increases sensitivity to docetaxel. STEAP1 was identified as the most translationally upregulated gene product in metastatic vs. non-metastatic gastric cancer cells by polysome profiling.\",\n      \"method\": \"Polysome profiling, siRNA/shRNA knockdown, overexpression plasmid, MTT/migration/invasion assays, xenograft mouse model\",\n      \"journal\": \"Frontiers in physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays with in vivo validation; single lab\",\n      \"pmids\": [\"30246786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Phosphorylated eIF4E controls cap-dependent translational upregulation of STEAP1 in gastric cancer cells undergoing peritoneal metastasis. Chemical inhibition or genetic ablation of eIF4E phosphorylation reduces STEAP1 protein levels, placing phospho-eIF4E upstream of STEAP1 in the translational control pathway.\",\n      \"method\": \"Chemical inhibitors of eIF4E phosphorylation, genetic eIF4E knockout, translational reporter assays, Western blot\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic approaches confirming eIF4E-mediated translational regulation of STEAP1; single lab\",\n      \"pmids\": [\"31949502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STEAP1 promotes gastric cancer cell proliferation, migration, and invasion via activation of the AKT/FoxO1 pathway and epithelial-mesenchymal transformation (EMT). Both overexpression and knockdown experiments confirmed these effects in vitro and in xenograft mouse models.\",\n      \"method\": \"Overexpression plasmid, lentiviral shRNA, CCK-8, flow cytometry, colony formation, transwell and wound healing assays, Western blot, subcutaneous and intraperitoneal xenograft\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with pathway analysis (AKT/FoxO1); single lab, multiple orthogonal methods\",\n      \"pmids\": [\"33128353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NKX2.2 is a transcriptional co-regulator of STEAP1 in Ewing's sarcoma. NKX2.2 binds to two sites in the STEAP1 promoter proximal to EWS/FLI1 binding sites and cooperatively upregulates STEAP1 expression together with EWS/FLI1.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), single-molecule RNA imaging, biochemical and genetic studies, promoter analysis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly confirms NKX2.2 binding to STEAP1 promoter; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34073779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"EFEMP1 directly promotes STEAP1 expression in osteosarcoma cells; knockdown of STEAP1 in EFEMP1-overexpressing cells significantly inhibits invasion, EMT, and Wnt/β-catenin and TGF-β/Smad2/3 signaling, placing STEAP1 downstream of EFEMP1 in these pathways. Exogenous EFEMP1 fails to activate these pathways when STEAP1 is knocked down.\",\n      \"method\": \"Overexpression and knockdown constructs, IHC, RT-qPCR, Western blot, in vitro invasion assays, epistasis experiments\",\n      \"journal\": \"Journal of bone oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — epistasis established by rescue experiment (EFEMP1 overexpression + STEAP1 knockdown); single lab\",\n      \"pmids\": [\"36388640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STEAP1 promotes ferroptosis in acute lung injury; inhibition of STEAP1 decreases ROS and MDA levels, increases Nrf2 and GSH levels, and affects the SLC7A11/GPX4 axis, suggesting STEAP1 modulates ferroptosis through this pathway.\",\n      \"method\": \"siRNA knockdown in HPMECs, LPS-induced ALI model, CLP mouse model, ROS/MDA/GSH/Fe2+ measurements, Western blot\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — loss-of-function in vitro and in vivo with mechanistic pathway readouts; single lab\",\n      \"pmids\": [\"37209327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14 and IGF2BP2 stabilize STEAP1 mRNA through m6A methylation modification. METTL14 silencing attenuates LPS-induced effects by decreasing STEAP1 expression. This m6A-dependent STEAP1 upregulation aggravates sepsis-induced acute lung injury.\",\n      \"method\": \"m6A RNA immunoprecipitation, dual-luciferase reporter assay, RNA immunoprecipitation, actinomycin D mRNA stability assay, siRNA knockdown, CLP rat model\",\n      \"journal\": \"Shock (Augusta, Ga.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — m6A RIP and RNA-IP directly confirm METTL14/IGF2BP2 interaction with STEAP1 mRNA; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"39193903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"STEAP1 depletion by RNAi in human mesenchymal stem cells (MSCs) results in decreased cell adhesion to tissue culture plastic, implicating STEAP1 in cell adhesion in MSCs.\",\n      \"method\": \"RNAi knockdown in human bone marrow MSCs, cell adhesion assay\",\n      \"journal\": \"Tissue engineering. Part A\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single functional readout (adhesion) with RNAi; single lab, limited mechanistic follow-up\",\n      \"pmids\": [\"19196137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A specific anti-STEAP1 scFv antibody binding to STEAP1 epitope significantly inhibits intercellular communication (dye transfer) between prostate cancer cells (PC3 and LNCaP) by ~80-90%, supporting STEAP1's role as a channel or transporter mediating gap junction-like intercellular communication.\",\n      \"method\": \"Phage library panning for scFv, ELISA, FACS, intercellular dye transfer (gap junction) assay\",\n      \"journal\": \"Anti-cancer agents in medicinal chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single functional assay with antibody blockade; single lab, indirect mechanistic inference\",\n      \"pmids\": [\"29219059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STEAP1 expression in prostate cancer is regulated by the androgen receptor (AR) in an AR-dependent manner in CWR22PC cells (in vitro and in vivo), demonstrated by ~66% decline in STEAP1 levels upon AR-targeted treatment monitored by 89Zr-immunoPET.\",\n      \"method\": \"89Zr-immunoPET imaging, in vitro and in vivo treatment with AR-targeting therapy, ELISA\",\n      \"journal\": \"Journal of nuclear medicine : official publication, Society of Nuclear Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct in vivo quantitative imaging plus in vitro validation; single lab, two orthogonal methods\",\n      \"pmids\": [\"25453051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"STEAP1 protein stability and mRNA stability differ between neoplastic (LNCaP) and non-neoplastic (PNT1A) prostate cells. Serum has opposite effects on STEAP1 stability in these two cell types, and in silico analysis predicts post-translational modifications including N-glycosylation, phosphorylation, and O-GlcNAcylation.\",\n      \"method\": \"mRNA and protein stability experiments, serum treatment, in silico PTM prediction\",\n      \"journal\": \"Genes & cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — stability assays are indirect; PTM predictions are computational; single lab\",\n      \"pmids\": [\"25053991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STEAP1 is selectively packaged into small extracellular vesicles (sEVs) from prostate cancer cells irrespective of androgen receptor (AR) status and cellular STEAP1 expression levels, indicating a selective EV-loading mechanism for STEAP1.\",\n      \"method\": \"Androgen deprivation/AR inhibition in multiple cell lines, Western blot and nanoparticle tracking of sEVs, ex vivo analysis in genetically engineered mice\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — describes selective EV packaging but mechanism of loading not determined; single lab\",\n      \"pmids\": [\"40287951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"STEAP1 overexpression in breast cancer cells inhibits cellular invasion and migration and reduces EMT marker expression (MMP2, MMP9, MMP13, VIM, CDH2), while increasing CDH1. Knockdown has the opposite effects. STEAP1 had little effect on proliferation in breast cancer cells.\",\n      \"method\": \"Overexpression and knockdown in breast cancer cell lines, transwell invasion/migration, Western blot for EMT markers\",\n      \"journal\": \"Clinical breast cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — reciprocal gain/loss-of-function with EMT pathway readout; single lab\",\n      \"pmids\": [\"30253922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"STEAP1 overexpression in oral squamous cell carcinoma (OSCC) cells inhibits proliferation, migration, invasion, and reduces intracellular ROS levels. Mechanistically, STEAP1 overexpression upregulates E-cadherin, downregulates N-cadherin (inhibiting EMT), and decreases β-catenin, Axin2, c-Myc, and p-GSK3β/T-GSK3β ratio (inhibiting Wnt/β-catenin signaling).\",\n      \"method\": \"Plasmid overexpression in OSCC cell lines, CCK-8, scratch, Transwell assays, ROS measurement, Western blot\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — gain-of-function only, pathway changes by Western blot; single lab, single method per readout\",\n      \"pmids\": [\"42046243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Proteomic analysis following STEAP1 siRNA knockdown in LNCaP prostate cancer cells identified 526 differentially expressed proteins; downstream pathways affected include endocytosis, apoptosis, and metabolic pathways. STEAP1 silencing specifically induced up-regulation of cathepsin B, intersectin-1, and syntaxin 4, and down-regulation of HRas, PIK3C2A, and DIS3.\",\n      \"method\": \"siRNA knockdown, label-free LC-MS/MS proteomics (Orbitrap), immunoblotting\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — unbiased proteomics plus immunoblot validation; single lab, two orthogonal methods\",\n      \"pmids\": [\"37315586\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STEAP1 is a six-transmembrane hemoprotein that assembles as a homotrimer (and heterotrimer with STEAP2/3/4) at the plasma membrane, binds a single b-type heme with histidine axial ligands and low-affinity FAD, and can support cross-membrane electron transfer to reduce Fe3+ and Cu2+ when provided an oxidoreductase domain (either via heterotrimer formation with STEAP2/3/4 or as a domain fusion), explaining its latent ferric/cupric reductase activity despite lacking an intrinsic NADPH-binding domain; in cancer cells, STEAP1 promotes proliferation, invasion, and EMT through ROS-mediated signaling and pathways including JAK2/STAT3, AKT/FoxO1, and Wnt/β-catenin, while its expression is regulated transcriptionally by EWS/FLI1 and NKX2.2, translationally by phospho-eIF4E, and post-transcriptionally by METTL14/IGF2BP2-mediated m6A modification.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STEAP1 is a six-transmembrane plasma-membrane hemoprotein, originally identified at cell-cell junctions of prostate secretory epithelium, that serves as a metalloreductase module within the STEAP family and as a driver of oncogenic phenotypes in multiple cancers [#1, #3, #7]. Biochemically, purified STEAP1 assembles as a homotrimer—and a heterotrimer with STEAP2—with each protomer binding a single b-type heme coordinated by histidine axial ligands, plus low-affinity FAD; in its ferrous state it reduces Fe3+ and Cu2+ and reacts with O2 by an outer-sphere redox mechanism [#3]. Unlike STEAP2/3/4, STEAP1 lacks an intracellular NADPH-binding oxidoreductase domain and shows no standalone cellular ferric reductase activity, but the cryo-EM structure reveals a reductase-like transmembrane fold, and STEAP1 gains ferric reductase activity when supplied an oxidoreductase domain—either fused to the STEAP4 NADPH domain, reconstituted with reduced FAD or cytochrome b5 reductase, or supplied diffusible FAD reduced by STEAP2—establishing it as a cross-membrane electron-transfer component dependent on partner subunits [#2, #4, #6]. In cancer, STEAP1 promotes proliferation, invasion, and epithelial-mesenchymal transition, acting through ROS-linked redox signaling and the JAK2/STAT3, AKT/FoxO1, and Wnt/\\u03b2-catenin pathways, with loss-of-function reducing tumor growth and metastasis in Ewing sarcoma, gastric, lung, and prostate models [#7, #10, #13, #24]. Its expression is controlled at multiple levels: transcriptionally by the EWS/FLI1 fusion oncoprotein cooperating with NKX2.2, and by the androgen receptor in prostate cancer; translationally by phospho-eIF4E; and post-transcriptionally by METTL14/IGF2BP2-mediated m6A mRNA stabilization [#7, #14, #20, #12, #17]. Notably, STEAP1 acts as a tumor suppressor in some contexts, with overexpression in breast and oral squamous carcinoma inhibiting invasion and EMT [#23, #24].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established STEAP1's existence and subcellular setting—a six-transmembrane protein at prostate epithelial cell-cell junctions—framing the initial hypothesis that it is a channel or transporter.\",\n      \"evidence\": \"cDNA subtraction cloning, IHC and cell-surface protein analysis across cancer cell lines\",\n      \"pmids\": [\"10588738\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No transport or enzymatic activity demonstrated\", \"Functional role of junctional localization unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated that STEAP2/3/4 are ferri/cupric reductases stimulating iron and copper uptake, while STEAP1 was negative in the same assay—defining the central puzzle of STEAP1's apparent lack of intrinsic reductase activity.\",\n      \"evidence\": \"Functional expression and cellular iron/copper uptake assays\",\n      \"pmids\": [\"16609065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not test whether STEAP1 is active with a supplied oxidoreductase partner\", \"No structural basis offered\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showed STEAP3 binds heme, FAD, and iron and transfers electrons through a single heme, with FAD/metal-binding motifs conserved in STEAP1—predicting latent oxidoreductase capacity for the domainless STEAP1.\",\n      \"evidence\": \"Biochemical reconstitution, mutagenesis, in vitro electron transfer on STEAP3 TMD\",\n      \"pmids\": [\"26205815\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"STEAP1 activity inferred from sequence conservation, not directly assayed\", \"Source of electrons for STEAP1 unaddressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Provided the first direct biochemical proof that mammalian STEAP1 is a homotrimeric hemoprotein that reduces Fe3+/Cu2+ in its ferrous state and forms heterotrimers with STEAP2, establishing the cofactor architecture.\",\n      \"evidence\": \"Milligram-scale purification of rabbit STEAP1, EPR/UV-vis spectroscopy, stopped-flow kinetics, co-expression\",\n      \"pmids\": [\"27792302\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological electron donor in cells not identified\", \"Did not resolve standalone vs. partner-dependent activity in cellular context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the cryo-EM structure of human STEAP1 and proved that, lacking an NADPH domain, it has no standalone ferric reductase activity but becomes active when fused to the STEAP4 NADPH domain—defining it as a partner-dependent reductase.\",\n      \"evidence\": \"Cryo-EM at 3.0 \\u00c5, cell-based enzymatic assays with STEAP1-STEAP4 fusion constructs\",\n      \"pmids\": [\"32409586\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether native heterotrimers form and function in vivo not directly shown\", \"Electron donor in physiological setting unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Directly demonstrated STEAP1 can support a cross-membrane electron transfer chain using surrogate oxidoreductases and showed FAD is diffusible between STEAP subunits, mechanistically completing the partner-dependent reductase model.\",\n      \"evidence\": \"In vitro electron transfer assays with purified proteins, FAD-transfer experiments, cryo-EM of STEAP2 (3.2 \\u00c5)\",\n      \"pmids\": [\"37983176\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of FAD diffusion between subunits not established\", \"Endogenous oxidoreductase partner not identified in cells\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected STEAP1 to tumor biology by showing knockdown reduces Ewing tumor growth, invasion, and metastasis, with effects linked to ROS and EWS/FLI1-driven expression—establishing a redox-coupled oncogenic role.\",\n      \"evidence\": \"RNAi, in vitro invasion/colony assays, xenografts, transcriptome/proteome, ROS measurement\",\n      \"pmids\": [\"22080479\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between reductase activity and ROS generation not demonstrated\", \"Downstream pro-invasive effectors only partly defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined cancer-context signaling routes for STEAP1, placing it upstream of JAK2/STAT3 in lung adenocarcinoma and of AKT/FoxO1 in gastric cancer to drive proliferation, migration, and EMT.\",\n      \"evidence\": \"siRNA/overexpression, pharmacological STAT3 inhibition (epistasis), migration/invasion assays, xenografts, Western blot\",\n      \"pmids\": [\"32515474\", \"33128353\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking STEAP1 to pathway activation unclear\", \"Single-lab findings per cancer type\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped layered regulation of STEAP1 expression—NKX2.2 cooperating with EWS/FLI1 transcriptionally, phospho-eIF4E translationally, and androgen receptor in prostate cancer—explaining its context-specific overexpression.\",\n      \"evidence\": \"ChIP and promoter analysis, eIF4E inhibition/knockout, AR-targeted treatment with 89Zr-immunoPET\",\n      \"pmids\": [\"34073779\", \"31949502\", \"25453051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each regulatory layer per tissue unknown\", \"Whether regulation feeds back to reductase function unaddressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended STEAP1 regulation to m6A epitranscriptomics, showing METTL14/IGF2BP2 stabilize STEAP1 mRNA and that this aggravates sepsis-induced acute lung injury via ferroptosis pathways.\",\n      \"evidence\": \"m6A-RIP, RNA-IP, mRNA stability assay, dual-luciferase reporter, siRNA, CLP rodent models\",\n      \"pmids\": [\"39193903\", \"37209327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which STEAP1 modulates SLC7A11/GPX4 axis not resolved\", \"Link between reductase activity and ferroptosis not directly tested\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified a context-dependent tumor-suppressive role, with STEAP1 overexpression inhibiting invasion, EMT, and Wnt/\\u03b2-catenin signaling in breast and oral squamous carcinoma—contrasting its oncogenic role elsewhere.\",\n      \"evidence\": \"Reciprocal overexpression/knockdown, transwell invasion, EMT marker and Wnt pathway Western blots, ROS measurement\",\n      \"pmids\": [\"30253922\", \"42046243\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Gain-of-function only in OSCC; single method per readout\", \"Mechanistic basis for opposite roles across tissues unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The identity of STEAP1's endogenous oxidoreductase partner in living cells, and the causal link between its metalloreductase/ROS activity and its divergent oncogenic versus tumor-suppressive signaling outputs, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No identified physiological electron donor in native cellular context\", \"No mechanism reconciling pro-tumor and anti-tumor phenotypes across tissues\", \"Direct test linking reductase catalysis to downstream signaling absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [3, 4, 6]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [4, 6]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 13]}\n    ],\n    \"complexes\": [\"STEAP1 homotrimer\", \"STEAP1/STEAP2 heterotrimer\"],\n    \"partners\": [\"STEAP2\", \"STEAP4\", \"METTL14\", \"IGF2BP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}