{"gene":"STEAP3","run_date":"2026-06-10T07:46:42","timeline":{"discoveries":[{"year":2003,"finding":"TSAP6/STEAP3 associates with Nix (a proapoptotic Bcl-2-related protein) and the Myt1 kinase (a negative regulator of the G2/M transition), as shown by yeast two-hybrid, GST pull-down, and in vivo co-immunoprecipitation. TSAP6 enhances susceptibility to apoptosis and cooperates with Nix to exacerbate apoptosis; it also augments Myt1 kinase activity to affect cell-cycle progression.","method":"Yeast two-hybrid, GST/in vitro pull-down, co-immunoprecipitation, siRNA knockdown, apoptosis and cell-cycle assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus yeast two-hybrid and GST pull-down, single lab with multiple orthogonal binding methods","pmids":["12606722"],"is_preprint":false},{"year":2004,"finding":"TSAP6/STEAP3 directly interacts with TCTP (translationally controlled tumor protein) and promotes its secretion via a non-classical, ER/Golgi-independent pathway involving exosomes. TSAP6 overexpression increases TCTP levels in exosome preparations, and both proteins co-distribute to vesicular-like structures at the plasma membrane and around the nucleus.","method":"Yeast two-hybrid, GST pull-down, immunofluorescence, overexpression-based secretion assay, exosome fractionation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding confirmed by two methods (yeast two-hybrid + GST pull-down), functional secretion assay, single lab","pmids":["15319436"],"is_preprint":false},{"year":2008,"finding":"TSAP6/STEAP3 is a glycosylated protein localized to the trans-Golgi network, endosomal-vesicular compartment, and cytoplasmic membrane. Genetic ablation of TSAP6 in mice severely compromises exosome production and abrogates the DNA damage-induced p53-dependent nonclassical exosomal secretory pathway. TSAP6-null mice exhibit microcytic anemia with deficient transferrin receptor downregulation (a process dependent on exosomal secretion).","method":"Knockout mouse model, immunofluorescence/subcellular fractionation, exosome quantification, hematologic analysis","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with multiple orthogonal phenotypic readouts (exosome quantification, anemia phenotype, transferrin receptor downregulation), independently consistent with parallel studies","pmids":["18617898"],"is_preprint":false},{"year":2008,"finding":"The crystal structure of the human STEAP3 oxidoreductase domain was determined in the absence and presence of NADPH. The structure reveals an FNO-like (archaeal oxidoreductase-like) domain with an unexpected dimer interface; substrate binding sites are positioned to direct electron transfer from cytosolic NADPH/flavin to a heme moiety in the transmembrane domain, consistent with its role as the dominant ferrireductase reducing Fe3+ to Fe2+ in erythroid endosomes.","method":"X-ray crystallography (crystal structure with and without NADPH), structural analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with ligand-bound and apo forms, defining the catalytic architecture","pmids":["18495927"],"is_preprint":false},{"year":2008,"finding":"A Y228H substitution in Steap3 (fragile-red mouse strain generated by ENU mutagenesis) identifies a conserved endosomal targeting motif required for Steap3 localization to internal compartments and for normal iron metabolism/erythropoiesis. Disruption of this motif causes hypochromic microcytic anemia.","method":"ENU mutagenesis screen, point mutant analysis, hematologic phenotyping, subcellular targeting assays","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional mutant in vivo with defined localization motif, single lab","pmids":["18955558"],"is_preprint":false},{"year":2012,"finding":"Steap3 is expressed at high levels in macrophages and hepatocytes and is required for normal intracellular iron homeostasis. Steap3 deficiency causes abnormal iron distribution and decreased cytosolic iron availability in macrophages, and impairs TLR4-mediated inflammatory signaling (reduced induction of interferon-β, MCP-5, and IP-10). Steap3 mRNA is uniquely downregulated among STEAP family members upon LPS stimulation.","method":"Steap3 knockout mouse, bone marrow-derived macrophage cultures, LPS stimulation, iron distribution assays, cytokine measurement","journal":"Haematologica","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple phenotypic readouts (iron homeostasis + immune signaling), single lab","pmids":["22689674"],"is_preprint":false},{"year":2012,"finding":"The rhomboid protease RHBDD1 cleaves TSAP6/STEAP3 in a dose- and activity-dependent manner at a major site in the C-terminal of the third transmembrane domain (identified by mass spectrometry and mutagenesis). Inactivation of RHBDD1 increases exosome secretion in colon cancer cells in a TSAP6-dependent manner, indicating that RHBDD1 regulates nonclassical exosomal trafficking through proteolytic restriction of TSAP6.","method":"Overexpression/knock-in of RHBDD1, mass spectrometry, mutagenesis of cleavage site, TSAP6 knockdown, exosome component detection (Tsg101, Tf-R, FasL, Trail)","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cleavage site mapped by MS and mutagenesis, epistasis experiment (TSAP6 knockdown reverses RHBDD1 KO phenotype), single lab","pmids":["22624035"],"is_preprint":false},{"year":2015,"finding":"In TSAP6/Steap3 knockout mice, the primary cause of microcytic anemia is abnormal erythroid maturation: there is a decreased number of proerythroblasts in bone marrow and impaired progression from proerythroblastic to orthochromatic stage with accumulation at the polychromatic stage. Decreased membrane mechanical stability was observed in knockout RBCs, but without significant changes in major skeletal/transmembrane protein expression or altered red cell survival.","method":"Knockout mouse model, comprehensive hematologic characterization, ektacytometry, flow cytometric analysis of erythropoiesis stages","journal":"American journal of hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with comprehensive multi-method erythropoiesis staging, single lab","pmids":["25515317"],"is_preprint":false},{"year":2019,"finding":"Genetic variation in Steap3 expression level is a critical determinant of oxidative damage to red blood cells during storage. Increased Steap3 levels promote lipid peroxidation-mediated degradation of the RBC membrane, leading to hemolysis and RBC clearance after transfusion.","method":"Metabolomics, genetics (QTL mapping across mouse strains), molecular and cellular biology (lipid peroxidation assays, hemolysis measurements)","journal":"Blood advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-strain genetics plus metabolomics and cellular assays, single lab but orthogonal approaches","pmids":["31350307"],"is_preprint":false},{"year":2019,"finding":"Oxidative stress-dependent upregulation of STEAP3 in wound fibroblasts is a key mediator of extracellular matrix deposition and remodeling during wound healing. Diabetic wounds display dysregulated STEAP3 expression and delayed ECM deposition.","method":"In vitro oxidative stress assays, gene expression modulation (knockdown/overexpression), ECM deposition and remodeling assays, diabetic mouse wound model","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional studies with loss/gain of STEAP3 and defined ECM readout, single lab","pmids":["31176711"],"is_preprint":false},{"year":2020,"finding":"STEAP3 directly binds to Rac1 (Rho family small GTPase 1) and suppresses activation of the downstream MAPK-ERK signaling cascade. In cardiomyocytes, STEAP3 deficiency exacerbates pressure overload-induced cardiac hypertrophy and fibrosis, while cardiomyocyte-specific overexpression is protective. The anti-hypertrophic effect of STEAP3 is blocked by constitutively active Rac1 (G12V), placing STEAP3 upstream of Rac1 in this pathway.","method":"Transverse aortic constriction mouse model, cardiac-specific STEAP3 KO and transgenic overexpression, RNA-seq, immunoprecipitation-mass spectrometry, constitutively active Rac1 rescue experiment","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO and OE with consistent reciprocal phenotypes, IP-MS identified Rac1 as binding partner, epistasis rescue experiment with constitutively active Rac1","pmids":["32862709"],"is_preprint":false},{"year":2021,"finding":"STEAP3 localizes to the nucleus of HCC cells (aberrant nuclear localization) and promotes cancer cell proliferation by facilitating nuclear trafficking of EGFR, which in turn enhances RAC1-ERK-STAT3 and RAC1-JNK-STAT6 signaling. STEAP3 participates in a positive feedback loop by upregulating EGFR expression and nuclear trafficking.","method":"Immunofluorescence/IHC for nuclear localization, HCC cell line gain/loss-of-function, signaling pathway analysis (EGFR, STAT3, RAC1), co-immunoprecipitation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — nuclear localization established by imaging, functional epistasis with EGFR, single lab","pmids":["34741044"],"is_preprint":false},{"year":2022,"finding":"Steap3 and LcytB (Cyb561a3) function as lysosomal ferrireductases in macrophages, converting Fe3+ to Fe2+ for iron recycling from ferritin-loaded lysosomes. CRISPR/Cas9 knockout of either reductase decreases lysosomal iron export; double knockout has an additive effect. Loss of both reductases increases DMT1 and Tfrc1 transcripts, indicating cellular iron limitation. Reduced Steap3/LcytB expression during E. coli infection correlates with increased intracellular bacterial proliferation, suggesting reductase downregulation is an innate immune strategy.","method":"CRISPR/Cas9 knockout, lysosomal iron export assay (cationic ferritin loading), transcript analysis of iron acquisition genes, bacterial infection assay","journal":"Blood advances","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR KO with functional iron export assay, additive double KO, in vitro and infection context, clear mechanistic readout","pmids":["34982827"],"is_preprint":false},{"year":2022,"finding":"STEAP3-mediated production of cellular ferrous iron (Fe2+) elevates Ser9 phosphorylation of GSK3β and inhibits its kinase activity, thereby releasing β-catenin for nuclear translocation and activating Wnt signaling in colorectal cancer cells.","method":"STEAP3 overexpression/knockdown in CRC cells, Fe2+ measurement, GSK3β phosphorylation assay, β-catenin nuclear translocation assay (immunofluorescence, Western blot)","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic chain established by functional assays in CRC cells, single lab; note this paper primarily concerns the lncRNA STEAP3-AS1 but the STEAP3 protein mechanism is experimentally validated","pmids":["35986274"],"is_preprint":false},{"year":2022,"finding":"STEAP3 knockdown in renal cell carcinoma cells sensitizes them to ferroptosis induced by erastin. This effect is mediated through the p53/xCT (SLC7A11) pathway, where reduced STEAP3 promotes p53 activity and downregulates xCT.","method":"STEAP3 knockdown in RCC cell lines, erastin-induced ferroptosis assay, Western blot for p53/xCT pathway components","journal":"Technology in cancer research & treatment","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pathway placement by Western blot without reconstitution or epistasis rescue","pmids":["35275508"],"is_preprint":false},{"year":2022,"finding":"Steap3 interacts with Gm2a (Ganglioside GM2 activator) to inhibit phagosomal escape of Listeria monocytogenes in macrophages. Steap3 deletion facilitates bacterial entry from phagosome to cytoplasm and alters lysosomal signaling pathway protein abundances. LLO secreted by L. monocytogenes (not the host) is responsible for decreased Steap3 abundance during infection.","method":"Quantitative proteomics, Steap3 deletion (functional assays), phagosomal escape assay, proteomic analysis of lysosomal pathway","journal":"Microbes and infection","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomics plus functional phagosomal escape assay with Steap3 deletion, identified Gm2a as relevant downstream protein, single lab","pmids":["35569749"],"is_preprint":false},{"year":2023,"finding":"STEAP3 physically binds to EGFR in lung squamous cell carcinoma cells (confirmed by co-immunoprecipitation). EGFR overexpression reverses the effects of STEAP3 silencing on cell viability, proliferation, oxidative stress, and ferroptosis, placing STEAP3 upstream of EGFR in LUSC.","method":"Co-immunoprecipitation, STEAP3 knockdown, EGFR overexpression rescue, cell viability/proliferation/oxidative stress/ferroptosis assays","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirmed binding plus epistasis rescue with EGFR overexpression, single lab","pmids":["38040224"],"is_preprint":false},{"year":2023,"finding":"STEAP3 interacts with Rab7A (suppressing its activity) and with RACK1 (enhancing its activity) in osteoarthritis. Suppression of Rab7A and promotion of RACK1 by STEAP3 activates receptor tyrosine kinases and downstream MAPK and JAK/STAT signaling, promoting inflammation.","method":"Transcriptomic and interaction proteomics, validated protein interactions (implied Co-IP/pulldown), signaling pathway assays in OA cartilage/cells","journal":"International immunopharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction proteomics with downstream pathway readouts, single lab, method detail limited in abstract","pmids":["37820423"],"is_preprint":false},{"year":2024,"finding":"STEAP3 knockdown in ovarian cancer cells induces ferroptosis through the p53/SLC7A11 (xCT) signaling pathway. Knockdown inhibits proliferation and migration, and suppresses tumor growth in nude mice via promotion of ferroptosis through p53.","method":"STEAP3 knockdown, ferroptosis indicator assays, Western blot for p53/SLC7A11 pathway, xenograft tumor growth assay","journal":"Mediators of inflammation","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional KD with ferroptosis assays and pathway marker Western blot, single lab, no reconstitution","pmids":["38440354"],"is_preprint":false},{"year":2024,"finding":"ATF3 is enriched at the STEAP3 gene locus (identified by ChIP-seq), and CRISPR/Cas9-mediated deletion of the ATF3 binding site suppresses STEAP3 expression. H3K27ac is significantly enriched at the STEAP3 gene, and STEAP3 knockdown downregulates H3K27ac, indicating STEAP3 expression is regulated by H3K27ac/ATF3 and STEAP3 in turn regulates histone acetylation.","method":"ChIP-seq, ChIP-qPCR, ATAC-seq, CRISPR/Cas9 ATF3 binding site deletion, Western blot","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq plus CRISPR-mediated binding site deletion, multiple orthogonal chromatin methods, single lab","pmids":["38480539"],"is_preprint":false},{"year":2024,"finding":"STEAP3 knockdown in cervical cancer cells suppresses JAK2 and STAT3 phosphorylation, reduces N-cadherin and vimentin, and increases E-cadherin, indicating STEAP3 promotes proliferation and EMT via the JAK/STAT3 pathway. STAT3 activator colivelin rescues STEAP3 knockdown phenotypes, placing STEAP3 upstream of JAK/STAT3.","method":"STEAP3 knockdown, RNA sequencing, Western blot for JAK/STAT3 and EMT markers, colivelin rescue experiment","journal":"Cancer & metabolism","confidence":"Low","confidence_rationale":"Tier 3 / Weak — KD plus one rescue experiment, pathway placement by Western blot, single lab","pmids":["39736751"],"is_preprint":false},{"year":2024,"finding":"M2 macrophage-derived exosomal circ_0088494 recruits histone-lysine N-methyltransferase KMT2D to promote H3K4me1 modification at the STEAP3 locus, thereby upregulating STEAP3 expression and inhibiting ferroptosis in cutaneous squamous cell carcinoma cells. This identifies H3K4me1 as a positive epigenetic regulator of STEAP3 expression.","method":"ChIP, RIP, western blot, RT-qPCR, ferroptosis assays (lipid-ROS, MDA, iron level), circ_0088494 silencing + STEAP3 overexpression rescue","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirmed H3K4me1 enrichment at STEAP3 locus, epistasis rescue confirms mechanistic order, single lab","pmids":["39692268"],"is_preprint":false},{"year":2025,"finding":"MDM2 overexpression reduces p53 protein levels and reduces STEAP3 protein expression in H9c2 cardiomyocytes under hypoxia/reoxygenation, while STEAP3 overexpression reverses the protective effects of MDM2 overexpression, placing STEAP3 downstream of the MDM2-p53 axis in cardiomyocyte injury.","method":"MDM2 and STEAP3 overexpression, Western blot for p53 and STEAP3, functional assays for oxidative damage, inflammation, apoptosis, ferroptosis","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — overexpression epistasis, Western blot only, single lab, mechanism inferred from rescue assays","pmids":["38640125"],"is_preprint":false},{"year":2025,"finding":"USP10 stabilizes IGF2BP3 by removing K48- and K63-linked ubiquitin chains. Stabilized IGF2BP3 binds STEAP3 mRNA and enhances its stability in an m6A-dependent manner. Upregulated STEAP3 suppresses ferroptosis by increasing glutathione levels and reducing lipid peroxidation, promoting tumor proliferation and gemcitabine resistance in pancreatic cancer.","method":"Gain/loss-of-function experiments, ubiquitin chain type analysis, m6A-dependent mRNA binding assay (IGF2BP3-STEAP3 mRNA), ferroptosis assays (GSH, lipid peroxidation)","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic chain with m6A mRNA stability assay and functional ferroptosis readout, single lab","pmids":["41381842"],"is_preprint":false},{"year":2025,"finding":"STEAP3 overexpression increases intracellular copper levels in TNBC cells, and STEAP3 knockdown decreases copper levels, indicating STEAP3 regulates intracellular copper homeostasis in addition to iron. Copper directly binds and activates CDK16 kinase, which then binds and activates JAK1 kinase to upregulate c-Myc and cyclin D1, promoting TNBC proliferation and metastasis.","method":"STEAP3 overexpression/knockdown with intracellular copper measurement, in vitro and in vivo tumor assays, copper chelator (tetrathiomolybdate) treatment, CDK16-JAK1 binding and activation assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional evidence for copper regulation by STEAP3 with downstream signaling cascade, in vitro and xenograft validation, single lab","pmids":["41338444"],"is_preprint":false},{"year":2025,"finding":"STEAP3 promotes TNBC progression by stabilizing FGFR1 protein and subsequently activating the PI3K/AKT/mTOR pathway. STEAP3 knockdown suppressed xenograft tumor growth and reduced proliferation markers.","method":"STEAP3 knockdown/overexpression, co-immunoprecipitation (implied by FGFR1 stabilization), PI3K/AKT/mTOR signaling assays, xenograft model","journal":"iScience","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional assays with signaling pathway readout but abstract does not detail binding confirmation method, single lab","pmids":["40487427"],"is_preprint":false},{"year":2025,"finding":"Steap3 interacts with both Gm2a and STING to inhibit phagosomal escape of Listeria monocytogenes in dendritic and intestinal epithelial cells. Steap3 deficiency exacerbates bacterial proliferation in vitro and in vivo. Steap3 expression is downregulated in these cells upon infection.","method":"Steap3 deletion (in vitro/in vivo), co-immunoprecipitation/interaction assays for Gm2a and STING, bacterial proliferation assays","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function in multiple cell types with defined binding partners and bacterial proliferation readout, single lab","pmids":["40252499"],"is_preprint":false},{"year":2025,"finding":"STEAP3 directly binds to CISD2 (a [2Fe-2S] cluster-containing mitochondrial protein) and stabilizes it. The flavonoid GL-V9 promotes STEAP3 degradation via the ubiquitin-proteasome pathway, which in turn destabilizes CISD2 and exacerbates oxidative stress and apoptosis in small cell lung cancer. STEAP3 overexpression attenuates ROS, mitochondrial damage, and apoptosis, while restoring CISD2 rescues cells from GL-V9 effects.","method":"Drug-target interaction analysis, STEAP3 overexpression/degradation assays, ubiquitin-proteasome pathway assay, CISD2 expression rescue, ROS/lipid peroxidation/mitochondrial function assays, xenograft model","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic chain with proteasomal degradation, CISD2 stabilization link, and rescue experiments, single lab","pmids":["41638446"],"is_preprint":false},{"year":2025,"finding":"MBD2 (methyl-CpG-binding domain 2) binds to the Steap3 promoter region and modulates its DNA methylation state in chondrocytes, suppressing Steap3 expression. Loss of MBD2 in cartilage-specific knockout mice induces Steap3-dependent ferroptosis (Fe3+→Fe2+ conversion) and exacerbates osteoarthritis. AAV-mediated Steap3 knockdown alleviates OA induced by MBD2 deletion.","method":"Cartilage-specific MBD2 KO mouse, RNA sequencing, CUT&Tag and RRBS for MBD2-Steap3 promoter methylation, AAV-Steap3 knockdown rescue, ferroptosis inhibitor experiment","journal":"Experimental & molecular medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo genetic KO with CUT&Tag promoter binding assay, RRBS methylation, and AAV rescue epistasis, multiple orthogonal methods in one study","pmids":["41258082"],"is_preprint":false},{"year":2025,"finding":"DON (deoxynivalenol) disrupts glycolysis, reduces lactate, and diminishes H3K18la (histone lactylation) via downregulation of the lactylation writer P300, which collectively suppresses STEAP3 expression. Reduced STEAP3 leads to intracellular iron accumulation, elevated lipid peroxidation, and GPX4 downregulation, triggering ferroptosis in porcine granulosa cells. Melatonin restores H3K18la and STEAP3 expression, suppressing ferroptosis.","method":"Multi-omics (transcriptomics + metabolomics), H3K18la ChIP, P300 assay, STEAP3 expression/functional assays, ferroptosis markers, melatonin rescue in vitro and in vivo","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics with ChIP for H3K18la at STEAP3, functional rescue, single lab","pmids":["41266595"],"is_preprint":false},{"year":2024,"finding":"TFAP2C transcription factor binds directly to the STEAP3 promoter and positively regulates its expression in lung squamous cell carcinoma. ChIP and luciferase reporter assays confirmed TFAP2C-STEAP3 promoter binding. TFAP2C knockdown anti-tumor effects are partially reversed by STEAP3 overexpression, placing TFAP2C upstream of STEAP3.","method":"ChIP assay, luciferase reporter assay, TFAP2C knockdown + STEAP3 overexpression rescue, in vivo tumor models","journal":"Biology direct","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and luciferase reporter, epistasis rescue, single lab","pmids":["39716275"],"is_preprint":false}],"current_model":"STEAP3 (TSAP6) is a p53-transcriptional-target, multi-pass transmembrane metalloreductase that catalyzes Fe3+-to-Fe2+ reduction in endosomes and lysosomes using a cytosolic FNO-like NADPH/flavin-binding oxidoreductase domain coupled to a heme-containing transmembrane domain (crystal structure established); it is required for efficient iron acquisition during erythropoiesis and lysosomal iron recycling in macrophages, controls exosome biogenesis and nonclassical secretion (including TCTP export), interacts with Nix/Myt1 to link apoptosis and cell-cycle control, binds Rac1 to suppress MAPK-ERK cardiac hypertrophy signaling, regulates copper homeostasis, and modulates ferroptosis susceptibility through the p53/xCT axis; its expression is epigenetically controlled by H3K27ac (ATF3), H3K4me1 (KMT2D), H3K18la (P300), and promoter DNA methylation (MBD2), and its protein stability is regulated by RHBDD1 (proteolysis) and the USP10-IGF2BP3 m6A axis."},"narrative":{"mechanistic_narrative":"STEAP3 (TSAP6) is a glycosylated multi-pass transmembrane metalloreductase that catalyzes the reduction of Fe3+ to Fe2+ within endosomal and lysosomal compartments, functioning as the dominant ferrireductase of erythroid iron acquisition [PMID:18495927, PMID:18955558]. Its crystallized cytosolic oxidoreductase domain adopts an FNO-like fold that channels electrons from NADPH/flavin to a heme moiety in the transmembrane domain, and a conserved endosomal-targeting motif (disrupted by the Y228H substitution) is required for its localization to internal compartments and for normal erythropoiesis [PMID:18495927, PMID:18955558]. Loss of STEAP3 causes microcytic anemia driven by impaired erythroid maturation, and the protein is independently required for lysosomal iron recycling in macrophages, where it acts redundantly with the ferrireductase LcytB to export iron from ferritin-loaded lysosomes [PMID:25515317, PMID:34982827]. Beyond iron handling, STEAP3 governs nonclassical exosomal secretion: it traffics through the trans-Golgi and endosomal-vesicular system, is required for p53-dependent DNA-damage-induced exosome production, and promotes the unconventional secretion of TCTP, with its rhomboid-protease (RHBDD1) cleavage restricting this trafficking [PMID:15319436, PMID:18617898, PMID:22624035]. STEAP3 also regulates intracellular copper homeostasis and engages signaling partners directly, binding Rac1 to suppress MAPK-ERK-driven cardiac hypertrophy [PMID:32862709, PMID:41338444]. Through its ferrous-iron-generating activity STEAP3 modulates ferroptosis susceptibility, and its expression is controlled both transcriptionally (ATF3/H3K27ac, KMT2D/H3K4me1, P300/H3K18la, MBD2-dependent promoter methylation, TFAP2C) and post-transcriptionally (USP10-IGF2BP3 m6A-dependent mRNA stabilization), integrating it into the p53 axis and diverse disease contexts including osteoarthritis and multiple cancers [PMID:32862709, PMID:38480539, PMID:39692268, PMID:41381842, PMID:41258082, PMID:41266595, PMID:39716275].","teleology":[{"year":2003,"claim":"Established the first molecular partners of TSAP6/STEAP3, linking it to apoptosis and cell-cycle control before any enzymatic role was known.","evidence":"Yeast two-hybrid, GST pull-down, and reciprocal Co-IP with Nix and Myt1, plus apoptosis/cell-cycle assays","pmids":["12606722"],"confidence":"Medium","gaps":["No structural or enzymatic basis for these interactions defined","Physiological relevance in vivo not established"]},{"year":2004,"claim":"Showed STEAP3 drives nonclassical, ER/Golgi-independent secretion by promoting TCTP export via exosomes, defining its vesicular trafficking role.","evidence":"Yeast two-hybrid, GST pull-down, immunofluorescence, and exosome fractionation in overexpression assays","pmids":["15319436"],"confidence":"Medium","gaps":["Mechanism of how STEAP3 loads cargo into exosomes unknown","Single-lab overexpression-based secretion readout"]},{"year":2008,"claim":"Genetic ablation defined STEAP3 as essential for p53-dependent exosome biogenesis and revealed an anemia phenotype, connecting trafficking to iron physiology.","evidence":"Knockout mouse with exosome quantification, transferrin receptor downregulation, and hematologic analysis","pmids":["18617898"],"confidence":"High","gaps":["Did not resolve whether anemia stems from ferrireductase loss or exosome defect","Direct molecular machinery of exosome control not defined"]},{"year":2008,"claim":"Solved the oxidoreductase-domain structure, establishing the catalytic architecture for NADPH/flavin-to-heme electron transfer underlying Fe3+ reduction.","evidence":"X-ray crystallography of the human STEAP3 oxidoreductase domain with and without NADPH","pmids":["18495927"],"confidence":"High","gaps":["Full-length transmembrane/heme domain not crystallized","Catalytic cycle not directly observed in cells"]},{"year":2008,"claim":"A point mutation identified the endosomal-targeting motif required for STEAP3 localization and iron metabolism, linking subcellular trafficking to function.","evidence":"ENU mutagenesis Y228H mutant with hematologic phenotyping and subcellular targeting assays","pmids":["18955558"],"confidence":"Medium","gaps":["Trafficking adaptors recognizing the motif unidentified","Single mutant strain"]},{"year":2012,"claim":"Extended STEAP3 function to macrophage iron homeostasis and innate immune signaling, and showed RHBDD1 proteolysis regulates STEAP3-dependent exosome secretion.","evidence":"Steap3 knockout macrophages with iron/cytokine assays; RHBDD1 cleavage-site mapping by MS/mutagenesis with TSAP6-dependent exosome epistasis","pmids":["22689674","22624035"],"confidence":"Medium","gaps":["Connection between iron status and TLR4 signaling mechanistically incomplete","Physiological trigger of RHBDD1 cleavage unknown"]},{"year":2015,"claim":"Resolved that STEAP3-null anemia arises from a specific erythroid maturation block rather than altered red cell survival, refining the developmental role.","evidence":"Knockout mouse erythropoiesis staging by flow cytometry and ektacytometry","pmids":["25515317"],"confidence":"Medium","gaps":["Molecular cause of polychromatic-stage arrest not defined","Link to ferrireductase activity not directly tested"]},{"year":2019,"claim":"Linked STEAP3 levels to oxidative red-cell damage and to fibroblast ECM remodeling, implicating it in redox-driven tissue responses.","evidence":"Multi-strain QTL/metabolomics with lipid peroxidation/hemolysis assays; oxidative-stress fibroblast and diabetic wound models","pmids":["31350307","31176711"],"confidence":"Medium","gaps":["Whether redox effects are due to ferrireductase activity per se not isolated","ECM mechanism downstream of STEAP3 unresolved"]},{"year":2020,"claim":"Identified Rac1 as a direct binding partner through which STEAP3 suppresses MAPK-ERK signaling and protects against cardiac hypertrophy, defining a signaling function distinct from iron reduction.","evidence":"Cardiac KO/transgenic mice, TAC model, IP-MS, and constitutively active Rac1 rescue epistasis","pmids":["32862709"],"confidence":"High","gaps":["Structural basis of STEAP3-Rac1 binding unknown","Whether metalloreductase activity is required for Rac1 suppression untested"]},{"year":2022,"claim":"Demonstrated STEAP3 acts as a lysosomal ferrireductase for macrophage iron recycling redundant with LcytB, and established a ferrous-iron-to-Wnt/GSK3β signaling axis in cancer.","evidence":"CRISPR single/double KO with lysosomal iron export assays; CRC functional assays of Fe2+, GSK3β phosphorylation, and β-catenin translocation","pmids":["34982827","35986274"],"confidence":"High","gaps":["Relative contribution of endosomal vs lysosomal reduction in vivo unresolved","Direct iron-GSK3β chemical mechanism not fully defined"]},{"year":2022,"claim":"Connected STEAP3 to ferroptosis modulation via the p53/xCT axis and to phagosomal containment of intracellular bacteria, broadening its roles in cell death and host defense.","evidence":"RCC STEAP3 knockdown with erastin ferroptosis and p53/xCT Western blot; Steap3-deletion proteomics with Listeria phagosomal escape assay identifying Gm2a","pmids":["35275508","35569749"],"confidence":"Medium","gaps":["p53/xCT placement rests on Western blot without reconstitution (idx 14, Low)","How STEAP3-Gm2a complex restricts escape mechanistically unknown"]},{"year":2024,"claim":"Defined a multi-layered transcriptional and epigenetic regulatory network controlling STEAP3 expression across tissues.","evidence":"ChIP-seq/CRISPR for ATF3/H3K27ac; ChIP/rescue for KMT2D/H3K4me1; ChIP/luciferase for TFAP2C, each with functional readouts","pmids":["38480539","39692268","39716275"],"confidence":"Medium","gaps":["How distinct regulators are coordinated in a single cell type unknown","Feedback from STEAP3 to chromatin marks not mechanistically resolved"]},{"year":2025,"claim":"Showed STEAP3 stability and downstream activity are controlled post-transcriptionally (USP10-IGF2BP3 m6A) and through protein interactions stabilizing CISD2 and FGFR1, integrating it into cancer redox and proliferation programs.","evidence":"Gain/loss-of-function with m6A mRNA-stability assays, ubiquitin-proteasome degradation assays, CISD2/FGFR1 stabilization and rescue experiments, xenografts","pmids":["41381842","41638446","40487427"],"confidence":"Medium","gaps":["FGFR1 binding confirmation method not detailed (idx 25, Low)","Whether ferrireductase activity is needed for partner stabilization untested"]},{"year":2025,"claim":"Established STEAP3 as a regulator of copper homeostasis and an MBD2-methylation-controlled driver of ferroptosis in osteoarthritis, expanding its metal-handling and disease scope.","evidence":"TNBC copper measurement with CDK16-JAK1 cascade and chelator treatment; cartilage-specific MBD2 KO with CUT&Tag/RRBS and AAV-Steap3 rescue","pmids":["41338444","41258082"],"confidence":"High","gaps":["Mechanism by which STEAP3 alters copper levels not biochemically defined","Whether copper and iron reduction share the same catalytic site unknown"]},{"year":null,"claim":"How a single endosomal/lysosomal metalloreductase mechanistically couples its NADPH-to-heme reductase chemistry to its diverse non-enzymatic activities (Rac1/EGFR signaling, exosome biogenesis, partner stabilization) remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experiment separates catalytic-dead STEAP3 from wild-type across its signaling roles","Full-length structure with transmembrane heme domain unsolved","Whether copper reduction uses the iron catalytic machinery untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016491","term_label":"oxidoreductase activity","supporting_discovery_ids":[3,4,12,13]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[3]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[12]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[12]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[3,12]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[12,24]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,6]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,28]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10]}],"complexes":[],"partners":["NIX","MYT1","TCTP","RHBDD1","RAC1","EGFR","CISD2","GM2A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q658P3","full_name":"Metalloreductase STEAP3","aliases":["Dudulin-2","Six-transmembrane epithelial antigen of prostate 3","Tumor suppressor-activated pathway protein 6","hTSAP6","pHyde","hpHyde"],"length_aa":488,"mass_kda":54.6,"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 (PubMed:26205815). Mediates sequential transmembrane electron transfer from NADPH to FAD and onto heme, and finally to the Fe(3+) chelate (By similarity). Can also reduce Cu(2+) to Cu(1+) (By similarity). Mediates efficient transferrin-dependent iron uptake in erythroid cells (By similarity). May play a role downstream of p53/TP53 to interface apoptosis and cell cycle progression (By similarity). Indirectly involved in exosome secretion by facilitating the secretion of proteins such as TCTP (PubMed:15319436, PubMed:16651434)","subcellular_location":"Endosome membrane","url":"https://www.uniprot.org/uniprotkb/Q658P3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/STEAP3","classification":"Not Classified","n_dependent_lines":60,"n_total_lines":1208,"dependency_fraction":0.04966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"TMED10","stoichiometry":0.2},{"gene":"TMED2","stoichiometry":0.2},{"gene":"VAMP3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/STEAP3","total_profiled":1310},"omim":[{"mim_id":"616740","title":"IMMUNODEFICIENCY 46; IMD46","url":"https://www.omim.org/entry/616740"},{"mim_id":"615234","title":"ANEMIA, HYPOCHROMIC MICROCYTIC, WITH IRON OVERLOAD 2; AHMIO2","url":"https://www.omim.org/entry/615234"},{"mim_id":"609671","title":"STEAP3 METALLOREDUCTASE; STEAP3","url":"https://www.omim.org/entry/609671"},{"mim_id":"600763","title":"TUMOR PROTEIN, TRANSLATIONALLY-CONTROLLED 1; TPT1","url":"https://www.omim.org/entry/600763"},{"mim_id":"206100","title":"ANEMIA, HYPOCHROMIC MICROCYTIC, WITH IRON OVERLOAD 1; AHMIO1","url":"https://www.omim.org/entry/206100"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":180.3},{"tissue":"parathyroid gland","ntpm":74.2}],"url":"https://www.proteinatlas.org/search/STEAP3"},"hgnc":{"alias_symbol":["TSAP6","dudlin-2","STMP3"],"prev_symbol":[]},"alphafold":{"accession":"Q658P3","domains":[{"cath_id":"3.40.50.720","chopping":"29-202","consensus_level":"high","plddt":95.143,"start":29,"end":202},{"cath_id":"1.20.120","chopping":"210-462","consensus_level":"high","plddt":94.1763,"start":210,"end":462}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q658P3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q658P3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q658P3-F1-predicted_aligned_error_v6.png","plddt_mean":89.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=STEAP3","jax_strain_url":"https://www.jax.org/strain/search?query=STEAP3"},"sequence":{"accession":"Q658P3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q658P3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q658P3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q658P3"}},"corpus_meta":[{"pmid":"18617898","id":"PMC_18617898","title":"Exosome 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Nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/32679543","citation_count":20,"is_preprint":false},{"pmid":"25515317","id":"PMC_25515317","title":"Abnormal erythroid maturation leads to microcytic anemia in the TSAP6/Steap3 null mouse model.","date":"2015","source":"American journal of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/25515317","citation_count":20,"is_preprint":false},{"pmid":"37064114","id":"PMC_37064114","title":"Upregulation of the ferroptosis-related STEAP3 gene is a specific predictor of poor triple-negative breast cancer patient outcomes.","date":"2023","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/37064114","citation_count":19,"is_preprint":false},{"pmid":"35083470","id":"PMC_35083470","title":"Iron homeostasis pathway DNA methylation trajectories reveal a role for STEAP3 metalloreductase in patient outcomes after aneurysmal subarachnoid hemorrhage.","date":"2021","source":"Epigenetics communications","url":"https://pubmed.ncbi.nlm.nih.gov/35083470","citation_count":16,"is_preprint":false},{"pmid":"19236508","id":"PMC_19236508","title":"Down-regulated expression of the TSAP6 protein in liver is associated with a transition from cirrhosis to hepatocellular carcinoma.","date":"2009","source":"Histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/19236508","citation_count":15,"is_preprint":false},{"pmid":"38480539","id":"PMC_38480539","title":"STEAP3 promotes colon cancer cell proliferation and migration via regulating histone acetylation.","date":"2024","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38480539","citation_count":13,"is_preprint":false},{"pmid":"37820423","id":"PMC_37820423","title":"Research of STEAP3 interaction with Rab7A and RACK1 to modulate the MAPK and JAK/STAT signaling in Osteoarthritis.","date":"2023","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37820423","citation_count":10,"is_preprint":false},{"pmid":"39692268","id":"PMC_39692268","title":"M2 Macrophage-Derived Exosomal circ_0088494 Inhibits Ferroptosis via Promoting H3K4me1 Modification of STEAP3 in Cutaneous Squamous Cell Carcinoma.","date":"2024","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/39692268","citation_count":10,"is_preprint":false},{"pmid":"37386521","id":"PMC_37386521","title":"Identification of STEAP3-based molecular subtype and risk model in ovarian cancer.","date":"2023","source":"Journal of ovarian research","url":"https://pubmed.ncbi.nlm.nih.gov/37386521","citation_count":9,"is_preprint":false},{"pmid":"39736751","id":"PMC_39736751","title":"Silencing of STEAP3 suppresses cervical cancer cell proliferation and migration via JAK/STAT3 signaling pathway.","date":"2024","source":"Cancer & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39736751","citation_count":8,"is_preprint":false},{"pmid":"40665344","id":"PMC_40665344","title":"The LncRNA STEAP3-AS1 promotes liver metastasis in colorectal cancer by regulating histone lactylation through chromatin remodelling.","date":"2025","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/40665344","citation_count":7,"is_preprint":false},{"pmid":"35569749","id":"PMC_35569749","title":"Label-free quantitative proteomics reveals the Steap3-Gm2a axis inhibiting the phagosomal escape of Listeria monocytogenes.","date":"2022","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/35569749","citation_count":7,"is_preprint":false},{"pmid":"38040224","id":"PMC_38040224","title":"Molecular characterization of STEAP3 in lung squamous cell carcinoma: Regulating EGFR to affect cell proliferation and ferroptosis.","date":"2023","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/38040224","citation_count":6,"is_preprint":false},{"pmid":"40005907","id":"PMC_40005907","title":"STEAP3 Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication by Regulating Fatty Acid and Lipid Droplet Synthesis.","date":"2025","source":"Veterinary sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40005907","citation_count":4,"is_preprint":false},{"pmid":"40522493","id":"PMC_40522493","title":"Plasma expression of antisense LncRNAs RBM5-AS1, VPS9D1-AS1 and STEAP3-AS1 as novel biomarkers for colorectal cancer diagnosis.","date":"2025","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/40522493","citation_count":4,"is_preprint":false},{"pmid":"40412729","id":"PMC_40412729","title":"STEAP3 alleviates inflammation and fibrosis via iron metabolism in ischemia/reperfusion-associated lung injury.","date":"2025","source":"Biochimica et biophysica acta. 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diseases","url":"https://pubmed.ncbi.nlm.nih.gov/42116186","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.02.27.640676","title":"Genetic architecture of the red blood cell proteome in genetically diverse mice reveals central role of hemoglobin beta cysteine redox status in maintaining circulating glutathione pools","date":"2025-03-04","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.27.640676","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":28874,"output_tokens":8313,"usd":0.105659,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17936,"output_tokens":4841,"usd":0.105353,"stage2_stop_reason":"end_turn"},"total_usd":0.211012,"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\": 2003,\n      \"finding\": \"TSAP6/STEAP3 associates with Nix (a proapoptotic Bcl-2-related protein) and the Myt1 kinase (a negative regulator of the G2/M transition), as shown by yeast two-hybrid, GST pull-down, and in vivo co-immunoprecipitation. TSAP6 enhances susceptibility to apoptosis and cooperates with Nix to exacerbate apoptosis; it also augments Myt1 kinase activity to affect cell-cycle progression.\",\n      \"method\": \"Yeast two-hybrid, GST/in vitro pull-down, co-immunoprecipitation, siRNA knockdown, apoptosis and cell-cycle assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus yeast two-hybrid and GST pull-down, single lab with multiple orthogonal binding methods\",\n      \"pmids\": [\"12606722\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"TSAP6/STEAP3 directly interacts with TCTP (translationally controlled tumor protein) and promotes its secretion via a non-classical, ER/Golgi-independent pathway involving exosomes. TSAP6 overexpression increases TCTP levels in exosome preparations, and both proteins co-distribute to vesicular-like structures at the plasma membrane and around the nucleus.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, immunofluorescence, overexpression-based secretion assay, exosome fractionation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding confirmed by two methods (yeast two-hybrid + GST pull-down), functional secretion assay, single lab\",\n      \"pmids\": [\"15319436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"TSAP6/STEAP3 is a glycosylated protein localized to the trans-Golgi network, endosomal-vesicular compartment, and cytoplasmic membrane. Genetic ablation of TSAP6 in mice severely compromises exosome production and abrogates the DNA damage-induced p53-dependent nonclassical exosomal secretory pathway. TSAP6-null mice exhibit microcytic anemia with deficient transferrin receptor downregulation (a process dependent on exosomal secretion).\",\n      \"method\": \"Knockout mouse model, immunofluorescence/subcellular fractionation, exosome quantification, hematologic analysis\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with multiple orthogonal phenotypic readouts (exosome quantification, anemia phenotype, transferrin receptor downregulation), independently consistent with parallel studies\",\n      \"pmids\": [\"18617898\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The crystal structure of the human STEAP3 oxidoreductase domain was determined in the absence and presence of NADPH. The structure reveals an FNO-like (archaeal oxidoreductase-like) domain with an unexpected dimer interface; substrate binding sites are positioned to direct electron transfer from cytosolic NADPH/flavin to a heme moiety in the transmembrane domain, consistent with its role as the dominant ferrireductase reducing Fe3+ to Fe2+ in erythroid endosomes.\",\n      \"method\": \"X-ray crystallography (crystal structure with and without NADPH), structural analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with ligand-bound and apo forms, defining the catalytic architecture\",\n      \"pmids\": [\"18495927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A Y228H substitution in Steap3 (fragile-red mouse strain generated by ENU mutagenesis) identifies a conserved endosomal targeting motif required for Steap3 localization to internal compartments and for normal iron metabolism/erythropoiesis. Disruption of this motif causes hypochromic microcytic anemia.\",\n      \"method\": \"ENU mutagenesis screen, point mutant analysis, hematologic phenotyping, subcellular targeting assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional mutant in vivo with defined localization motif, single lab\",\n      \"pmids\": [\"18955558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Steap3 is expressed at high levels in macrophages and hepatocytes and is required for normal intracellular iron homeostasis. Steap3 deficiency causes abnormal iron distribution and decreased cytosolic iron availability in macrophages, and impairs TLR4-mediated inflammatory signaling (reduced induction of interferon-β, MCP-5, and IP-10). Steap3 mRNA is uniquely downregulated among STEAP family members upon LPS stimulation.\",\n      \"method\": \"Steap3 knockout mouse, bone marrow-derived macrophage cultures, LPS stimulation, iron distribution assays, cytokine measurement\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple phenotypic readouts (iron homeostasis + immune signaling), single lab\",\n      \"pmids\": [\"22689674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The rhomboid protease RHBDD1 cleaves TSAP6/STEAP3 in a dose- and activity-dependent manner at a major site in the C-terminal of the third transmembrane domain (identified by mass spectrometry and mutagenesis). Inactivation of RHBDD1 increases exosome secretion in colon cancer cells in a TSAP6-dependent manner, indicating that RHBDD1 regulates nonclassical exosomal trafficking through proteolytic restriction of TSAP6.\",\n      \"method\": \"Overexpression/knock-in of RHBDD1, mass spectrometry, mutagenesis of cleavage site, TSAP6 knockdown, exosome component detection (Tsg101, Tf-R, FasL, Trail)\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cleavage site mapped by MS and mutagenesis, epistasis experiment (TSAP6 knockdown reverses RHBDD1 KO phenotype), single lab\",\n      \"pmids\": [\"22624035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In TSAP6/Steap3 knockout mice, the primary cause of microcytic anemia is abnormal erythroid maturation: there is a decreased number of proerythroblasts in bone marrow and impaired progression from proerythroblastic to orthochromatic stage with accumulation at the polychromatic stage. Decreased membrane mechanical stability was observed in knockout RBCs, but without significant changes in major skeletal/transmembrane protein expression or altered red cell survival.\",\n      \"method\": \"Knockout mouse model, comprehensive hematologic characterization, ektacytometry, flow cytometric analysis of erythropoiesis stages\",\n      \"journal\": \"American journal of hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with comprehensive multi-method erythropoiesis staging, single lab\",\n      \"pmids\": [\"25515317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Genetic variation in Steap3 expression level is a critical determinant of oxidative damage to red blood cells during storage. Increased Steap3 levels promote lipid peroxidation-mediated degradation of the RBC membrane, leading to hemolysis and RBC clearance after transfusion.\",\n      \"method\": \"Metabolomics, genetics (QTL mapping across mouse strains), molecular and cellular biology (lipid peroxidation assays, hemolysis measurements)\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-strain genetics plus metabolomics and cellular assays, single lab but orthogonal approaches\",\n      \"pmids\": [\"31350307\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Oxidative stress-dependent upregulation of STEAP3 in wound fibroblasts is a key mediator of extracellular matrix deposition and remodeling during wound healing. Diabetic wounds display dysregulated STEAP3 expression and delayed ECM deposition.\",\n      \"method\": \"In vitro oxidative stress assays, gene expression modulation (knockdown/overexpression), ECM deposition and remodeling assays, diabetic mouse wound model\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional studies with loss/gain of STEAP3 and defined ECM readout, single lab\",\n      \"pmids\": [\"31176711\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"STEAP3 directly binds to Rac1 (Rho family small GTPase 1) and suppresses activation of the downstream MAPK-ERK signaling cascade. In cardiomyocytes, STEAP3 deficiency exacerbates pressure overload-induced cardiac hypertrophy and fibrosis, while cardiomyocyte-specific overexpression is protective. The anti-hypertrophic effect of STEAP3 is blocked by constitutively active Rac1 (G12V), placing STEAP3 upstream of Rac1 in this pathway.\",\n      \"method\": \"Transverse aortic constriction mouse model, cardiac-specific STEAP3 KO and transgenic overexpression, RNA-seq, immunoprecipitation-mass spectrometry, constitutively active Rac1 rescue experiment\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO and OE with consistent reciprocal phenotypes, IP-MS identified Rac1 as binding partner, epistasis rescue experiment with constitutively active Rac1\",\n      \"pmids\": [\"32862709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"STEAP3 localizes to the nucleus of HCC cells (aberrant nuclear localization) and promotes cancer cell proliferation by facilitating nuclear trafficking of EGFR, which in turn enhances RAC1-ERK-STAT3 and RAC1-JNK-STAT6 signaling. STEAP3 participates in a positive feedback loop by upregulating EGFR expression and nuclear trafficking.\",\n      \"method\": \"Immunofluorescence/IHC for nuclear localization, HCC cell line gain/loss-of-function, signaling pathway analysis (EGFR, STAT3, RAC1), co-immunoprecipitation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — nuclear localization established by imaging, functional epistasis with EGFR, single lab\",\n      \"pmids\": [\"34741044\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Steap3 and LcytB (Cyb561a3) function as lysosomal ferrireductases in macrophages, converting Fe3+ to Fe2+ for iron recycling from ferritin-loaded lysosomes. CRISPR/Cas9 knockout of either reductase decreases lysosomal iron export; double knockout has an additive effect. Loss of both reductases increases DMT1 and Tfrc1 transcripts, indicating cellular iron limitation. Reduced Steap3/LcytB expression during E. coli infection correlates with increased intracellular bacterial proliferation, suggesting reductase downregulation is an innate immune strategy.\",\n      \"method\": \"CRISPR/Cas9 knockout, lysosomal iron export assay (cationic ferritin loading), transcript analysis of iron acquisition genes, bacterial infection assay\",\n      \"journal\": \"Blood advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR KO with functional iron export assay, additive double KO, in vitro and infection context, clear mechanistic readout\",\n      \"pmids\": [\"34982827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STEAP3-mediated production of cellular ferrous iron (Fe2+) elevates Ser9 phosphorylation of GSK3β and inhibits its kinase activity, thereby releasing β-catenin for nuclear translocation and activating Wnt signaling in colorectal cancer cells.\",\n      \"method\": \"STEAP3 overexpression/knockdown in CRC cells, Fe2+ measurement, GSK3β phosphorylation assay, β-catenin nuclear translocation assay (immunofluorescence, Western blot)\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic chain established by functional assays in CRC cells, single lab; note this paper primarily concerns the lncRNA STEAP3-AS1 but the STEAP3 protein mechanism is experimentally validated\",\n      \"pmids\": [\"35986274\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"STEAP3 knockdown in renal cell carcinoma cells sensitizes them to ferroptosis induced by erastin. This effect is mediated through the p53/xCT (SLC7A11) pathway, where reduced STEAP3 promotes p53 activity and downregulates xCT.\",\n      \"method\": \"STEAP3 knockdown in RCC cell lines, erastin-induced ferroptosis assay, Western blot for p53/xCT pathway components\",\n      \"journal\": \"Technology in cancer research & treatment\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pathway placement by Western blot without reconstitution or epistasis rescue\",\n      \"pmids\": [\"35275508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Steap3 interacts with Gm2a (Ganglioside GM2 activator) to inhibit phagosomal escape of Listeria monocytogenes in macrophages. Steap3 deletion facilitates bacterial entry from phagosome to cytoplasm and alters lysosomal signaling pathway protein abundances. LLO secreted by L. monocytogenes (not the host) is responsible for decreased Steap3 abundance during infection.\",\n      \"method\": \"Quantitative proteomics, Steap3 deletion (functional assays), phagosomal escape assay, proteomic analysis of lysosomal pathway\",\n      \"journal\": \"Microbes and infection\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomics plus functional phagosomal escape assay with Steap3 deletion, identified Gm2a as relevant downstream protein, single lab\",\n      \"pmids\": [\"35569749\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STEAP3 physically binds to EGFR in lung squamous cell carcinoma cells (confirmed by co-immunoprecipitation). EGFR overexpression reverses the effects of STEAP3 silencing on cell viability, proliferation, oxidative stress, and ferroptosis, placing STEAP3 upstream of EGFR in LUSC.\",\n      \"method\": \"Co-immunoprecipitation, STEAP3 knockdown, EGFR overexpression rescue, cell viability/proliferation/oxidative stress/ferroptosis assays\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirmed binding plus epistasis rescue with EGFR overexpression, single lab\",\n      \"pmids\": [\"38040224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"STEAP3 interacts with Rab7A (suppressing its activity) and with RACK1 (enhancing its activity) in osteoarthritis. Suppression of Rab7A and promotion of RACK1 by STEAP3 activates receptor tyrosine kinases and downstream MAPK and JAK/STAT signaling, promoting inflammation.\",\n      \"method\": \"Transcriptomic and interaction proteomics, validated protein interactions (implied Co-IP/pulldown), signaling pathway assays in OA cartilage/cells\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction proteomics with downstream pathway readouts, single lab, method detail limited in abstract\",\n      \"pmids\": [\"37820423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STEAP3 knockdown in ovarian cancer cells induces ferroptosis through the p53/SLC7A11 (xCT) signaling pathway. Knockdown inhibits proliferation and migration, and suppresses tumor growth in nude mice via promotion of ferroptosis through p53.\",\n      \"method\": \"STEAP3 knockdown, ferroptosis indicator assays, Western blot for p53/SLC7A11 pathway, xenograft tumor growth assay\",\n      \"journal\": \"Mediators of inflammation\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional KD with ferroptosis assays and pathway marker Western blot, single lab, no reconstitution\",\n      \"pmids\": [\"38440354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATF3 is enriched at the STEAP3 gene locus (identified by ChIP-seq), and CRISPR/Cas9-mediated deletion of the ATF3 binding site suppresses STEAP3 expression. H3K27ac is significantly enriched at the STEAP3 gene, and STEAP3 knockdown downregulates H3K27ac, indicating STEAP3 expression is regulated by H3K27ac/ATF3 and STEAP3 in turn regulates histone acetylation.\",\n      \"method\": \"ChIP-seq, ChIP-qPCR, ATAC-seq, CRISPR/Cas9 ATF3 binding site deletion, Western blot\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq plus CRISPR-mediated binding site deletion, multiple orthogonal chromatin methods, single lab\",\n      \"pmids\": [\"38480539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"STEAP3 knockdown in cervical cancer cells suppresses JAK2 and STAT3 phosphorylation, reduces N-cadherin and vimentin, and increases E-cadherin, indicating STEAP3 promotes proliferation and EMT via the JAK/STAT3 pathway. STAT3 activator colivelin rescues STEAP3 knockdown phenotypes, placing STEAP3 upstream of JAK/STAT3.\",\n      \"method\": \"STEAP3 knockdown, RNA sequencing, Western blot for JAK/STAT3 and EMT markers, colivelin rescue experiment\",\n      \"journal\": \"Cancer & metabolism\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — KD plus one rescue experiment, pathway placement by Western blot, single lab\",\n      \"pmids\": [\"39736751\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"M2 macrophage-derived exosomal circ_0088494 recruits histone-lysine N-methyltransferase KMT2D to promote H3K4me1 modification at the STEAP3 locus, thereby upregulating STEAP3 expression and inhibiting ferroptosis in cutaneous squamous cell carcinoma cells. This identifies H3K4me1 as a positive epigenetic regulator of STEAP3 expression.\",\n      \"method\": \"ChIP, RIP, western blot, RT-qPCR, ferroptosis assays (lipid-ROS, MDA, iron level), circ_0088494 silencing + STEAP3 overexpression rescue\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirmed H3K4me1 enrichment at STEAP3 locus, epistasis rescue confirms mechanistic order, single lab\",\n      \"pmids\": [\"39692268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MDM2 overexpression reduces p53 protein levels and reduces STEAP3 protein expression in H9c2 cardiomyocytes under hypoxia/reoxygenation, while STEAP3 overexpression reverses the protective effects of MDM2 overexpression, placing STEAP3 downstream of the MDM2-p53 axis in cardiomyocyte injury.\",\n      \"method\": \"MDM2 and STEAP3 overexpression, Western blot for p53 and STEAP3, functional assays for oxidative damage, inflammation, apoptosis, ferroptosis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — overexpression epistasis, Western blot only, single lab, mechanism inferred from rescue assays\",\n      \"pmids\": [\"38640125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"USP10 stabilizes IGF2BP3 by removing K48- and K63-linked ubiquitin chains. Stabilized IGF2BP3 binds STEAP3 mRNA and enhances its stability in an m6A-dependent manner. Upregulated STEAP3 suppresses ferroptosis by increasing glutathione levels and reducing lipid peroxidation, promoting tumor proliferation and gemcitabine resistance in pancreatic cancer.\",\n      \"method\": \"Gain/loss-of-function experiments, ubiquitin chain type analysis, m6A-dependent mRNA binding assay (IGF2BP3-STEAP3 mRNA), ferroptosis assays (GSH, lipid peroxidation)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic chain with m6A mRNA stability assay and functional ferroptosis readout, single lab\",\n      \"pmids\": [\"41381842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STEAP3 overexpression increases intracellular copper levels in TNBC cells, and STEAP3 knockdown decreases copper levels, indicating STEAP3 regulates intracellular copper homeostasis in addition to iron. Copper directly binds and activates CDK16 kinase, which then binds and activates JAK1 kinase to upregulate c-Myc and cyclin D1, promoting TNBC proliferation and metastasis.\",\n      \"method\": \"STEAP3 overexpression/knockdown with intracellular copper measurement, in vitro and in vivo tumor assays, copper chelator (tetrathiomolybdate) treatment, CDK16-JAK1 binding and activation assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional evidence for copper regulation by STEAP3 with downstream signaling cascade, in vitro and xenograft validation, single lab\",\n      \"pmids\": [\"41338444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STEAP3 promotes TNBC progression by stabilizing FGFR1 protein and subsequently activating the PI3K/AKT/mTOR pathway. STEAP3 knockdown suppressed xenograft tumor growth and reduced proliferation markers.\",\n      \"method\": \"STEAP3 knockdown/overexpression, co-immunoprecipitation (implied by FGFR1 stabilization), PI3K/AKT/mTOR signaling assays, xenograft model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional assays with signaling pathway readout but abstract does not detail binding confirmation method, single lab\",\n      \"pmids\": [\"40487427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Steap3 interacts with both Gm2a and STING to inhibit phagosomal escape of Listeria monocytogenes in dendritic and intestinal epithelial cells. Steap3 deficiency exacerbates bacterial proliferation in vitro and in vivo. Steap3 expression is downregulated in these cells upon infection.\",\n      \"method\": \"Steap3 deletion (in vitro/in vivo), co-immunoprecipitation/interaction assays for Gm2a and STING, bacterial proliferation assays\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function in multiple cell types with defined binding partners and bacterial proliferation readout, single lab\",\n      \"pmids\": [\"40252499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"STEAP3 directly binds to CISD2 (a [2Fe-2S] cluster-containing mitochondrial protein) and stabilizes it. The flavonoid GL-V9 promotes STEAP3 degradation via the ubiquitin-proteasome pathway, which in turn destabilizes CISD2 and exacerbates oxidative stress and apoptosis in small cell lung cancer. STEAP3 overexpression attenuates ROS, mitochondrial damage, and apoptosis, while restoring CISD2 rescues cells from GL-V9 effects.\",\n      \"method\": \"Drug-target interaction analysis, STEAP3 overexpression/degradation assays, ubiquitin-proteasome pathway assay, CISD2 expression rescue, ROS/lipid peroxidation/mitochondrial function assays, xenograft model\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic chain with proteasomal degradation, CISD2 stabilization link, and rescue experiments, single lab\",\n      \"pmids\": [\"41638446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"MBD2 (methyl-CpG-binding domain 2) binds to the Steap3 promoter region and modulates its DNA methylation state in chondrocytes, suppressing Steap3 expression. Loss of MBD2 in cartilage-specific knockout mice induces Steap3-dependent ferroptosis (Fe3+→Fe2+ conversion) and exacerbates osteoarthritis. AAV-mediated Steap3 knockdown alleviates OA induced by MBD2 deletion.\",\n      \"method\": \"Cartilage-specific MBD2 KO mouse, RNA sequencing, CUT&Tag and RRBS for MBD2-Steap3 promoter methylation, AAV-Steap3 knockdown rescue, ferroptosis inhibitor experiment\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo genetic KO with CUT&Tag promoter binding assay, RRBS methylation, and AAV rescue epistasis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"41258082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DON (deoxynivalenol) disrupts glycolysis, reduces lactate, and diminishes H3K18la (histone lactylation) via downregulation of the lactylation writer P300, which collectively suppresses STEAP3 expression. Reduced STEAP3 leads to intracellular iron accumulation, elevated lipid peroxidation, and GPX4 downregulation, triggering ferroptosis in porcine granulosa cells. Melatonin restores H3K18la and STEAP3 expression, suppressing ferroptosis.\",\n      \"method\": \"Multi-omics (transcriptomics + metabolomics), H3K18la ChIP, P300 assay, STEAP3 expression/functional assays, ferroptosis markers, melatonin rescue in vitro and in vivo\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics with ChIP for H3K18la at STEAP3, functional rescue, single lab\",\n      \"pmids\": [\"41266595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TFAP2C transcription factor binds directly to the STEAP3 promoter and positively regulates its expression in lung squamous cell carcinoma. ChIP and luciferase reporter assays confirmed TFAP2C-STEAP3 promoter binding. TFAP2C knockdown anti-tumor effects are partially reversed by STEAP3 overexpression, placing TFAP2C upstream of STEAP3.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, TFAP2C knockdown + STEAP3 overexpression rescue, in vivo tumor models\",\n      \"journal\": \"Biology direct\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding confirmed by ChIP and luciferase reporter, epistasis rescue, single lab\",\n      \"pmids\": [\"39716275\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"STEAP3 (TSAP6) is a p53-transcriptional-target, multi-pass transmembrane metalloreductase that catalyzes Fe3+-to-Fe2+ reduction in endosomes and lysosomes using a cytosolic FNO-like NADPH/flavin-binding oxidoreductase domain coupled to a heme-containing transmembrane domain (crystal structure established); it is required for efficient iron acquisition during erythropoiesis and lysosomal iron recycling in macrophages, controls exosome biogenesis and nonclassical secretion (including TCTP export), interacts with Nix/Myt1 to link apoptosis and cell-cycle control, binds Rac1 to suppress MAPK-ERK cardiac hypertrophy signaling, regulates copper homeostasis, and modulates ferroptosis susceptibility through the p53/xCT axis; its expression is epigenetically controlled by H3K27ac (ATF3), H3K4me1 (KMT2D), H3K18la (P300), and promoter DNA methylation (MBD2), and its protein stability is regulated by RHBDD1 (proteolysis) and the USP10-IGF2BP3 m6A axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"STEAP3 (TSAP6) is a glycosylated multi-pass transmembrane metalloreductase that catalyzes the reduction of Fe3+ to Fe2+ within endosomal and lysosomal compartments, functioning as the dominant ferrireductase of erythroid iron acquisition [#3, #4]. Its crystallized cytosolic oxidoreductase domain adopts an FNO-like fold that channels electrons from NADPH/flavin to a heme moiety in the transmembrane domain, and a conserved endosomal-targeting motif (disrupted by the Y228H substitution) is required for its localization to internal compartments and for normal erythropoiesis [#3, #4]. Loss of STEAP3 causes microcytic anemia driven by impaired erythroid maturation, and the protein is independently required for lysosomal iron recycling in macrophages, where it acts redundantly with the ferrireductase LcytB to export iron from ferritin-loaded lysosomes [#7, #12]. Beyond iron handling, STEAP3 governs nonclassical exosomal secretion: it traffics through the trans-Golgi and endosomal-vesicular system, is required for p53-dependent DNA-damage-induced exosome production, and promotes the unconventional secretion of TCTP, with its rhomboid-protease (RHBDD1) cleavage restricting this trafficking [#1, #2, #6]. STEAP3 also regulates intracellular copper homeostasis and engages signaling partners directly, binding Rac1 to suppress MAPK-ERK-driven cardiac hypertrophy [#10, #24]. Through its ferrous-iron-generating activity STEAP3 modulates ferroptosis susceptibility, and its expression is controlled both transcriptionally (ATF3/H3K27ac, KMT2D/H3K4me1, P300/H3K18la, MBD2-dependent promoter methylation, TFAP2C) and post-transcriptionally (USP10-IGF2BP3 m6A-dependent mRNA stabilization), integrating it into the p53 axis and diverse disease contexts including osteoarthritis and multiple cancers [#10, #19, #21, #23, #28, #29, #30].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established the first molecular partners of TSAP6/STEAP3, linking it to apoptosis and cell-cycle control before any enzymatic role was known.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, and reciprocal Co-IP with Nix and Myt1, plus apoptosis/cell-cycle assays\",\n      \"pmids\": [\"12606722\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural or enzymatic basis for these interactions defined\", \"Physiological relevance in vivo not established\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed STEAP3 drives nonclassical, ER/Golgi-independent secretion by promoting TCTP export via exosomes, defining its vesicular trafficking role.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, immunofluorescence, and exosome fractionation in overexpression assays\",\n      \"pmids\": [\"15319436\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of how STEAP3 loads cargo into exosomes unknown\", \"Single-lab overexpression-based secretion readout\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Genetic ablation defined STEAP3 as essential for p53-dependent exosome biogenesis and revealed an anemia phenotype, connecting trafficking to iron physiology.\",\n      \"evidence\": \"Knockout mouse with exosome quantification, transferrin receptor downregulation, and hematologic analysis\",\n      \"pmids\": [\"18617898\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether anemia stems from ferrireductase loss or exosome defect\", \"Direct molecular machinery of exosome control not defined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Solved the oxidoreductase-domain structure, establishing the catalytic architecture for NADPH/flavin-to-heme electron transfer underlying Fe3+ reduction.\",\n      \"evidence\": \"X-ray crystallography of the human STEAP3 oxidoreductase domain with and without NADPH\",\n      \"pmids\": [\"18495927\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length transmembrane/heme domain not crystallized\", \"Catalytic cycle not directly observed in cells\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"A point mutation identified the endosomal-targeting motif required for STEAP3 localization and iron metabolism, linking subcellular trafficking to function.\",\n      \"evidence\": \"ENU mutagenesis Y228H mutant with hematologic phenotyping and subcellular targeting assays\",\n      \"pmids\": [\"18955558\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking adaptors recognizing the motif unidentified\", \"Single mutant strain\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended STEAP3 function to macrophage iron homeostasis and innate immune signaling, and showed RHBDD1 proteolysis regulates STEAP3-dependent exosome secretion.\",\n      \"evidence\": \"Steap3 knockout macrophages with iron/cytokine assays; RHBDD1 cleavage-site mapping by MS/mutagenesis with TSAP6-dependent exosome epistasis\",\n      \"pmids\": [\"22689674\", \"22624035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Connection between iron status and TLR4 signaling mechanistically incomplete\", \"Physiological trigger of RHBDD1 cleavage unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Resolved that STEAP3-null anemia arises from a specific erythroid maturation block rather than altered red cell survival, refining the developmental role.\",\n      \"evidence\": \"Knockout mouse erythropoiesis staging by flow cytometry and ektacytometry\",\n      \"pmids\": [\"25515317\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular cause of polychromatic-stage arrest not defined\", \"Link to ferrireductase activity not directly tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Linked STEAP3 levels to oxidative red-cell damage and to fibroblast ECM remodeling, implicating it in redox-driven tissue responses.\",\n      \"evidence\": \"Multi-strain QTL/metabolomics with lipid peroxidation/hemolysis assays; oxidative-stress fibroblast and diabetic wound models\",\n      \"pmids\": [\"31350307\", \"31176711\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether redox effects are due to ferrireductase activity per se not isolated\", \"ECM mechanism downstream of STEAP3 unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified Rac1 as a direct binding partner through which STEAP3 suppresses MAPK-ERK signaling and protects against cardiac hypertrophy, defining a signaling function distinct from iron reduction.\",\n      \"evidence\": \"Cardiac KO/transgenic mice, TAC model, IP-MS, and constitutively active Rac1 rescue epistasis\",\n      \"pmids\": [\"32862709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of STEAP3-Rac1 binding unknown\", \"Whether metalloreductase activity is required for Rac1 suppression untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrated STEAP3 acts as a lysosomal ferrireductase for macrophage iron recycling redundant with LcytB, and established a ferrous-iron-to-Wnt/GSK3\\u03b2 signaling axis in cancer.\",\n      \"evidence\": \"CRISPR single/double KO with lysosomal iron export assays; CRC functional assays of Fe2+, GSK3\\u03b2 phosphorylation, and \\u03b2-catenin translocation\",\n      \"pmids\": [\"34982827\", \"35986274\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of endosomal vs lysosomal reduction in vivo unresolved\", \"Direct iron-GSK3\\u03b2 chemical mechanism not fully defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected STEAP3 to ferroptosis modulation via the p53/xCT axis and to phagosomal containment of intracellular bacteria, broadening its roles in cell death and host defense.\",\n      \"evidence\": \"RCC STEAP3 knockdown with erastin ferroptosis and p53/xCT Western blot; Steap3-deletion proteomics with Listeria phagosomal escape assay identifying Gm2a\",\n      \"pmids\": [\"35275508\", \"35569749\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"p53/xCT placement rests on Western blot without reconstitution (idx 14, Low)\", \"How STEAP3-Gm2a complex restricts escape mechanistically unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a multi-layered transcriptional and epigenetic regulatory network controlling STEAP3 expression across tissues.\",\n      \"evidence\": \"ChIP-seq/CRISPR for ATF3/H3K27ac; ChIP/rescue for KMT2D/H3K4me1; ChIP/luciferase for TFAP2C, each with functional readouts\",\n      \"pmids\": [\"38480539\", \"39692268\", \"39716275\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How distinct regulators are coordinated in a single cell type unknown\", \"Feedback from STEAP3 to chromatin marks not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showed STEAP3 stability and downstream activity are controlled post-transcriptionally (USP10-IGF2BP3 m6A) and through protein interactions stabilizing CISD2 and FGFR1, integrating it into cancer redox and proliferation programs.\",\n      \"evidence\": \"Gain/loss-of-function with m6A mRNA-stability assays, ubiquitin-proteasome degradation assays, CISD2/FGFR1 stabilization and rescue experiments, xenografts\",\n      \"pmids\": [\"41381842\", \"41638446\", \"40487427\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"FGFR1 binding confirmation method not detailed (idx 25, Low)\", \"Whether ferrireductase activity is needed for partner stabilization untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established STEAP3 as a regulator of copper homeostasis and an MBD2-methylation-controlled driver of ferroptosis in osteoarthritis, expanding its metal-handling and disease scope.\",\n      \"evidence\": \"TNBC copper measurement with CDK16-JAK1 cascade and chelator treatment; cartilage-specific MBD2 KO with CUT&Tag/RRBS and AAV-Steap3 rescue\",\n      \"pmids\": [\"41338444\", \"41258082\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which STEAP3 alters copper levels not biochemically defined\", \"Whether copper and iron reduction share the same catalytic site unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single endosomal/lysosomal metalloreductase mechanistically couples its NADPH-to-heme reductase chemistry to its diverse non-enzymatic activities (Rac1/EGFR signaling, exosome biogenesis, partner stabilization) remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experiment separates catalytic-dead STEAP3 from wild-type across its signaling roles\", \"Full-length structure with transmembrane heme domain unsolved\", \"Whether copper reduction uses the iron catalytic machinery untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [3, 4, 12, 13]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 12]},\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [12, 24]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 6]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 28]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NIX\", \"MYT1\", \"TCTP\", \"RHBDD1\", \"RAC1\", \"EGFR\", \"CISD2\", \"GM2A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}