Affinage

STEAP3

Metalloreductase STEAP3 · UniProt Q658P3

Length
488 aa
Mass
54.6 kDa
Annotated
2026-06-10
50 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2003 Medium

    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

    PMID:12606722

    Open questions at the time
    • No structural or enzymatic basis for these interactions defined
    • Physiological relevance in vivo not established
  2. 2004 Medium

    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

    PMID:15319436

    Open questions at the time
    • Mechanism of how STEAP3 loads cargo into exosomes unknown
    • Single-lab overexpression-based secretion readout
  3. 2008 High

    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

    PMID:18617898

    Open questions at the time
    • Did not resolve whether anemia stems from ferrireductase loss or exosome defect
    • Direct molecular machinery of exosome control not defined
  4. 2008 High

    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

    PMID:18495927

    Open questions at the time
    • Full-length transmembrane/heme domain not crystallized
    • Catalytic cycle not directly observed in cells
  5. 2008 Medium

    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

    PMID:18955558

    Open questions at the time
    • Trafficking adaptors recognizing the motif unidentified
    • Single mutant strain
  6. 2012 Medium

    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

    PMID:22624035 PMID:22689674

    Open questions at the time
    • Connection between iron status and TLR4 signaling mechanistically incomplete
    • Physiological trigger of RHBDD1 cleavage unknown
  7. 2015 Medium

    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

    PMID:25515317

    Open questions at the time
    • Molecular cause of polychromatic-stage arrest not defined
    • Link to ferrireductase activity not directly tested
  8. 2019 Medium

    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

    PMID:31176711 PMID:31350307

    Open questions at the time
    • Whether redox effects are due to ferrireductase activity per se not isolated
    • ECM mechanism downstream of STEAP3 unresolved
  9. 2020 High

    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

    PMID:32862709

    Open questions at the time
    • Structural basis of STEAP3-Rac1 binding unknown
    • Whether metalloreductase activity is required for Rac1 suppression untested
  10. 2022 High

    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

    PMID:34982827 PMID:35986274

    Open questions at the time
    • Relative contribution of endosomal vs lysosomal reduction in vivo unresolved
    • Direct iron-GSK3β chemical mechanism not fully defined
  11. 2022 Medium

    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

    PMID:35275508 PMID:35569749

    Open questions at the time
    • p53/xCT placement rests on Western blot without reconstitution (idx 14, Low)
    • How STEAP3-Gm2a complex restricts escape mechanistically unknown
  12. 2024 Medium

    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

    PMID:38480539 PMID:39692268 PMID:39716275

    Open questions at the time
    • How distinct regulators are coordinated in a single cell type unknown
    • Feedback from STEAP3 to chromatin marks not mechanistically resolved
  13. 2025 Medium

    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

    PMID:40487427 PMID:41381842 PMID:41638446

    Open questions at the time
    • FGFR1 binding confirmation method not detailed (idx 25, Low)
    • Whether ferrireductase activity is needed for partner stabilization untested
  14. 2025 High

    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

    PMID:41258082 PMID:41338444

    Open questions at the time
    • Mechanism by which STEAP3 alters copper levels not biochemically defined
    • Whether copper and iron reduction share the same catalytic site unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 4 GO:0005215 transporter activity 1 GO:0140657 ATP-dependent activity 1
Localization
GO:0005768 endosome 2 GO:0005886 plasma membrane 2 GO:0031410 cytoplasmic vesicle 2 GO:0005764 lysosome 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1430728 Metabolism 2 R-HSA-382551 Transport of small molecules 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-162582 Signal Transduction 1
Partners
CISD2EGFRGM2AMYT1NIXRAC1RHBDD1TCTP

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 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. Yeast two-hybrid, GST/in vitro pull-down, co-immunoprecipitation, siRNA knockdown, apoptosis and cell-cycle assays Proceedings of the National Academy of Sciences of the United States of America Medium 12606722
2004 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. Yeast two-hybrid, GST pull-down, immunofluorescence, overexpression-based secretion assay, exosome fractionation The Journal of biological chemistry Medium 15319436
2008 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). Knockout mouse model, immunofluorescence/subcellular fractionation, exosome quantification, hematologic analysis Cell death and differentiation High 18617898
2008 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. X-ray crystallography (crystal structure with and without NADPH), structural analysis Proceedings of the National Academy of Sciences of the United States of America High 18495927
2008 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. ENU mutagenesis screen, point mutant analysis, hematologic phenotyping, subcellular targeting assays Blood Medium 18955558
2012 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. Steap3 knockout mouse, bone marrow-derived macrophage cultures, LPS stimulation, iron distribution assays, cytokine measurement Haematologica Medium 22689674
2012 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. Overexpression/knock-in of RHBDD1, mass spectrometry, mutagenesis of cleavage site, TSAP6 knockdown, exosome component detection (Tsg101, Tf-R, FasL, Trail) PloS one Medium 22624035
2015 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. Knockout mouse model, comprehensive hematologic characterization, ektacytometry, flow cytometric analysis of erythropoiesis stages American journal of hematology Medium 25515317
2019 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. Metabolomics, genetics (QTL mapping across mouse strains), molecular and cellular biology (lipid peroxidation assays, hemolysis measurements) Blood advances Medium 31350307
2019 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. In vitro oxidative stress assays, gene expression modulation (knockdown/overexpression), ECM deposition and remodeling assays, diabetic mouse wound model The Journal of investigative dermatology Medium 31176711
2020 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. Transverse aortic constriction mouse model, cardiac-specific STEAP3 KO and transgenic overexpression, RNA-seq, immunoprecipitation-mass spectrometry, constitutively active Rac1 rescue experiment Hypertension (Dallas, Tex. : 1979) High 32862709
2021 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. Immunofluorescence/IHC for nuclear localization, HCC cell line gain/loss-of-function, signaling pathway analysis (EGFR, STAT3, RAC1), co-immunoprecipitation Cell death & disease Medium 34741044
2022 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. CRISPR/Cas9 knockout, lysosomal iron export assay (cationic ferritin loading), transcript analysis of iron acquisition genes, bacterial infection assay Blood advances High 34982827
2022 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. STEAP3 overexpression/knockdown in CRC cells, Fe2+ measurement, GSK3β phosphorylation assay, β-catenin nuclear translocation assay (immunofluorescence, Western blot) Molecular cancer Medium 35986274
2022 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. STEAP3 knockdown in RCC cell lines, erastin-induced ferroptosis assay, Western blot for p53/xCT pathway components Technology in cancer research & treatment Low 35275508
2022 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. Quantitative proteomics, Steap3 deletion (functional assays), phagosomal escape assay, proteomic analysis of lysosomal pathway Microbes and infection Medium 35569749
2023 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. Co-immunoprecipitation, STEAP3 knockdown, EGFR overexpression rescue, cell viability/proliferation/oxidative stress/ferroptosis assays Archives of biochemistry and biophysics Medium 38040224
2023 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. Transcriptomic and interaction proteomics, validated protein interactions (implied Co-IP/pulldown), signaling pathway assays in OA cartilage/cells International immunopharmacology Low 37820423
2024 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. STEAP3 knockdown, ferroptosis indicator assays, Western blot for p53/SLC7A11 pathway, xenograft tumor growth assay Mediators of inflammation Low 38440354
2024 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. ChIP-seq, ChIP-qPCR, ATAC-seq, CRISPR/Cas9 ATF3 binding site deletion, Western blot Human genetics Medium 38480539
2024 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. STEAP3 knockdown, RNA sequencing, Western blot for JAK/STAT3 and EMT markers, colivelin rescue experiment Cancer & metabolism Low 39736751
2024 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. ChIP, RIP, western blot, RT-qPCR, ferroptosis assays (lipid-ROS, MDA, iron level), circ_0088494 silencing + STEAP3 overexpression rescue Molecular carcinogenesis Medium 39692268
2025 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. MDM2 and STEAP3 overexpression, Western blot for p53 and STEAP3, functional assays for oxidative damage, inflammation, apoptosis, ferroptosis PloS one Low 38640125
2025 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. Gain/loss-of-function experiments, ubiquitin chain type analysis, m6A-dependent mRNA binding assay (IGF2BP3-STEAP3 mRNA), ferroptosis assays (GSH, lipid peroxidation) Oncogene Medium 41381842
2025 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. STEAP3 overexpression/knockdown with intracellular copper measurement, in vitro and in vivo tumor assays, copper chelator (tetrathiomolybdate) treatment, CDK16-JAK1 binding and activation assays Cancer letters Medium 41338444
2025 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. STEAP3 knockdown/overexpression, co-immunoprecipitation (implied by FGFR1 stabilization), PI3K/AKT/mTOR signaling assays, xenograft model iScience Low 40487427
2025 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. Steap3 deletion (in vitro/in vivo), co-immunoprecipitation/interaction assays for Gm2a and STING, bacterial proliferation assays Molecular immunology Medium 40252499
2025 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. Drug-target interaction analysis, STEAP3 overexpression/degradation assays, ubiquitin-proteasome pathway assay, CISD2 expression rescue, ROS/lipid peroxidation/mitochondrial function assays, xenograft model Free radical biology & medicine Medium 41638446
2025 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. Cartilage-specific MBD2 KO mouse, RNA sequencing, CUT&Tag and RRBS for MBD2-Steap3 promoter methylation, AAV-Steap3 knockdown rescue, ferroptosis inhibitor experiment Experimental & molecular medicine High 41258082
2025 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. Multi-omics (transcriptomics + metabolomics), H3K18la ChIP, P300 assay, STEAP3 expression/functional assays, ferroptosis markers, melatonin rescue in vitro and in vivo Communications biology Medium 41266595
2024 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. ChIP assay, luciferase reporter assay, TFAP2C knockdown + STEAP3 overexpression rescue, in vivo tumor models Biology direct Medium 39716275

Source papers

Stage 0 corpus · 50 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Exosome secretion, including the DNA damage-induced p53-dependent secretory pathway, is severely compromised in TSAP6/Steap3-null mice. Cell death and differentiation 293 18617898
2004 TSAP6 facilitates the secretion of translationally controlled tumor protein/histamine-releasing factor via a nonclassical pathway. The Journal of biological chemistry 177 15319436
2022 Hypoxia-induced lncRNA STEAP3-AS1 activates Wnt/β-catenin signaling to promote colorectal cancer progression by preventing m6A-mediated degradation of STEAP3 mRNA. Molecular cancer 129 35986274
2012 Metalloreductase Steap3 coordinates the regulation of iron homeostasis and inflammatory responses. Haematologica 107 22689674
2003 The p53-inducible TSAP6 gene product regulates apoptosis and the cell cycle and interacts with Nix and the Myt1 kinase. Proceedings of the National Academy of Sciences of the United States of America 95 12606722
2008 Structure of the membrane proximal oxidoreductase domain of human Steap3, the dominant ferrireductase of the erythroid transferrin cycle. Proceedings of the National Academy of Sciences of the United States of America 94 18495927
2008 Identification of a Steap3 endosomal targeting motif essential for normal iron metabolism. Blood 85 18955558
2019 Differences in Steap3 expression are a mechanism of genetic variation of RBC storage and oxidative damage in mice. Blood advances 80 31350307
2022 STEAP3 Affects Ferroptosis and Progression of Renal Cell Carcinoma Through the p53/xCT Pathway. Technology in cancer research & treatment 57 35275508
2021 STEAP3 promotes cancer cell proliferation by facilitating nuclear trafficking of EGFR to enhance RAC1-ERK-STAT3 signaling in hepatocellular carcinoma. Cell death & disease 49 34741044
2022 Lysosomal iron recycling in mouse macrophages is dependent upon both LcytB and Steap3 reductases. Blood advances 44 34982827
2011 A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene. Blood 44 22031863
2019 Reduced Iron in Diabetic Wounds: An Oxidative Stress-Dependent Role for STEAP3 in Extracellular Matrix Deposition and Remodeling. The Journal of investigative dermatology 39 31176711
2011 Human STEAP3 maintains tumor growth under hypoferric condition. Experimental cell research 38 21871451
2012 Exosome-related multi-pass transmembrane protein TSAP6 is a target of rhomboid protease RHBDD1-induced proteolysis. PloS one 33 22624035
2022 Matrix stiffness-dependent STEAP3 coordinated with PD-L2 identify tumor responding to sorafenib treatment in hepatocellular carcinoma. Cancer cell international 32 36229881
2020 STEAP3 (Six-Transmembrane Epithelial Antigen of Prostate 3) Inhibits Pathological Cardiac Hypertrophy. Hypertension (Dallas, Tex. : 1979) 31 32862709
2024 STEAP3 Affects Ovarian Cancer Progression by Regulating Ferroptosis through the p53/SLC7A11 Pathway. Mediators of inflammation 24 38440354
2019 Molecular chaperone HspB2 inhibited pancreatic cancer cell proliferation via activating p53 downstream gene RPRM, BAI1, and TSAP6. Journal of cellular biochemistry 23 31692031
2020 lncRNA STEAP3-AS1 Modulates Cell Cycle Progression via Affecting CDKN1C Expression through STEAP3 in Colon Cancer. Molecular therapy. Nucleic acids 20 32679543
2015 Abnormal erythroid maturation leads to microcytic anemia in the TSAP6/Steap3 null mouse model. American journal of hematology 20 25515317
2023 Upregulation of the ferroptosis-related STEAP3 gene is a specific predictor of poor triple-negative breast cancer patient outcomes. Frontiers in oncology 19 37064114
2021 Iron homeostasis pathway DNA methylation trajectories reveal a role for STEAP3 metalloreductase in patient outcomes after aneurysmal subarachnoid hemorrhage. Epigenetics communications 16 35083470
2009 Down-regulated expression of the TSAP6 protein in liver is associated with a transition from cirrhosis to hepatocellular carcinoma. Histopathology 15 19236508
2024 STEAP3 promotes colon cancer cell proliferation and migration via regulating histone acetylation. Human genetics 13 38480539
2024 M2 Macrophage-Derived Exosomal circ_0088494 Inhibits Ferroptosis via Promoting H3K4me1 Modification of STEAP3 in Cutaneous Squamous Cell Carcinoma. Molecular carcinogenesis 10 39692268
2023 Research of STEAP3 interaction with Rab7A and RACK1 to modulate the MAPK and JAK/STAT signaling in Osteoarthritis. International immunopharmacology 10 37820423
2023 Identification of STEAP3-based molecular subtype and risk model in ovarian cancer. Journal of ovarian research 9 37386521
2024 Silencing of STEAP3 suppresses cervical cancer cell proliferation and migration via JAK/STAT3 signaling pathway. Cancer & metabolism 8 39736751
2025 The LncRNA STEAP3-AS1 promotes liver metastasis in colorectal cancer by regulating histone lactylation through chromatin remodelling. Journal of experimental & clinical cancer research : CR 7 40665344
2022 Label-free quantitative proteomics reveals the Steap3-Gm2a axis inhibiting the phagosomal escape of Listeria monocytogenes. Microbes and infection 7 35569749
2023 Molecular characterization of STEAP3 in lung squamous cell carcinoma: Regulating EGFR to affect cell proliferation and ferroptosis. Archives of biochemistry and biophysics 6 38040224
2025 STEAP3 Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication by Regulating Fatty Acid and Lipid Droplet Synthesis. Veterinary sciences 4 40005907
2025 Plasma expression of antisense LncRNAs RBM5-AS1, VPS9D1-AS1 and STEAP3-AS1 as novel biomarkers for colorectal cancer diagnosis. Molecular biology reports 4 40522493
2025 Steap3 is a key node in regulating the phagosome escape of Listeria monocytogenes. Molecular immunology 3 40252499
2025 STEAP3 alleviates inflammation and fibrosis via iron metabolism in ischemia/reperfusion-associated lung injury. Biochimica et biophysica acta. Molecular basis of disease 3 40412729
2025 STEAP3 promotes triple-negative breast cancer growth through the FGFR1-mediated activation of PI3K/AKT/mTOR signaling. iScience 2 40487427
2025 Deoxynivalenol induces ferroptosis via inhibiting glycolysis-H3K18la-STEAP3 axis to promote ovary damage in piglets. Communications biology 2 41266595
2024 TFAP2C-mediated transcriptional activation of STEAP3 promotes lung squamous cell carcinoma progression by regulating the β-catenin pathway. Biology direct 2 39716275
2026 The flavonoid GL-V9 induces oxidative stress mediated apoptosis in small cell lung cancer by promoting STEAP3 degradation. Free radical biology & medicine 1 41638446
2025 Methyl-CpG-binding domain 2 mitigates osteoarthritis through Steap3 promoter methylation and chondrocyte ferroptosis regulation. Experimental & molecular medicine 1 41258082
2025 Copper orchestrates triple-negative breast cancer progression via the STEAP3-dependent CDK16-JAK1 activation. Cancer letters 1 41338444
2025 USP10 promotes cell proliferation and gemcitabine resistance in pancreatic cancer by the regulation of IGF2BP3-STEAP3. Oncogene 1 41381842
2024 Xinnaotongluo liquid protects H9c2 cells from H/R-induced damage by regulating MDM2/STEAP3. PloS one 1 38640125
2024 STEAP3-SLC39A8-mediated microglia ferroptosis involved in neurotoxicity in rats after exposure to lead and cadmium combined. International immunopharmacology 1 39708487
2026 Biallelic STEAP3 Variant in Neonatal Hemophagocytic Lymphohistiocytosis. Clinical genetics 0 41556408
2026 A case of mixed histiocytosis (Erdheim-Chester disease and Langerhans cell histiocytosis) with STEAP3-associated anemia and type 4 hemochromatosis. Orphanet journal of rare diseases 0 42116186
2025 miR-507 Acts as a Tumor Suppressor in Renal Cell Carcinoma Cells by Targeting STEAP3. Combinatorial chemistry & high throughput screening 0 39806969
2025 Integration of biomimetic organoid-on-chip and 2D models advances the mechanistic Understanding of STEAP3-mediated regulation in intestinal viral infection. Scientific reports 0 40836050
2025 (+)-Strebloside induces Non-Hodgkin lymphoma cell death through the STEAP3-Mediated Ferroptosis and MAPK pathway. Chinese journal of natural medicines 0 41073062

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