{"gene":"TFRC","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2015,"finding":"A homozygous p.Tyr20His substitution in TfR1 disrupts the TfR1 internalization motif, resulting in defective receptor endocytosis and markedly increased TfR1 surface expression; iron citrate rescued lymphocyte defects, and wild-type but not mutant TfR1 rescued impaired transferrin uptake in patient-derived fibroblasts. STEAP3, a metalloreductase expressed in erythroblasts, was shown to associate with TfR1 and partially rescue transferrin uptake, suggesting an accessory endocytosis signal.","method":"Patient-derived fibroblast rescue assay, Co-IP, Tfrc(Y20H/Y20H) knock-in mouse model, endocytosis assays","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (patient cells, mouse model, rescue with WT vs mutant, Co-IP for STEAP3 interaction), single rigorous study with strong controls","pmids":["26642240"],"is_preprint":false},{"year":2015,"finding":"Stearic acid (C18:0) stearoylates TfR1 (TFRC), thereby inhibiting TfR1-mediated activation of JNK signaling. This reduces ubiquitination of mitofusin via HUWE1, promoting mitochondrial fusion and function. Dietary C18:0 intake modulates this pathway in vivo.","method":"In vivo dietary manipulation, Drosophila genetic model, biochemical stearoylation assay, JNK signaling readouts, mitofusin ubiquitination assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — pathway dissected with multiple orthogonal methods (biochemistry, genetics, in vivo dietary intervention), published in high-quality journal with rigorous controls","pmids":["26214738"],"is_preprint":false},{"year":2013,"finding":"TfR1 physically interacts with the IKK complex. TfR1 depletion reduces IKK complex formation and inhibits TNFα-induced NF-κB-dependent transcription; NF-κB fails to translocate to the nucleus efficiently, reducing target gene promoter binding and increasing apoptosis in response to TNFα.","method":"Unbiased proteomics screen, Co-IP, siRNA knockdown, NF-κB reporter assay, chromatin binding assay, apoptosis assay","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus functional readouts (NF-κB nuclear translocation, promoter binding, apoptosis), single lab with multiple orthogonal methods","pmids":["23016877"],"is_preprint":false},{"year":2017,"finding":"Overexpression of TfR1 in β-thalassemic erythroid precursors contributes to ineffective erythropoiesis and iron overload. Apotransferrin inhibits TfR1 expression independently of erythropoietin and iron-related signaling, decreases TfR1 partitioning to reticulocytes during enucleation, and enhances enucleation. Haploinsufficiency of TfR1 (TfR1+/-) crossed into β-thalassemic mice reverses iron overload and improves hepcidin derepression.","method":"Mouse genetic crosses (TfR1+/- × β-thalassemia), in vitro erythroid culture with apotransferrin, flow cytometry, in vivo iron measurements","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model combined with in vitro mechanistic dissection, multiple orthogonal endpoints, replicated across conditions","pmids":["28151426"],"is_preprint":false},{"year":2023,"finding":"Hepatocyte TfR1 interacts with HFE to regulate hepcidin production. Hepatocyte-specific Tfrc knockout in mice leads to reduced serum/liver iron and inappropriately elevated hepcidin relative to iron status, but ablation of hepatocyte Tfrc has no impact on iron phenotype in Hfe knockout mice, demonstrating that TfR1's nonredundant function in systemic iron homeostasis depends on HFE. Ablation of hepatocyte Tfrc in β-thalassemia mice ameliorates hepcidin deficiency and liver iron loading.","method":"Hepatocyte-specific conditional Tfrc knockout mice (Tfrcfl/fl;Alb-Cre+), double knockout with Hfe, β-thalassemia mouse model, serum/liver iron measurements, hepcidin quantification","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout genetics with multiple disease models and epistasis analysis, rigorous in vivo study","pmids":["36322932"],"is_preprint":false},{"year":2021,"finding":"TRIB2 desensitizes cells to ferroptosis via the E3 ubiquitin ligase βTrCP, which ubiquitinates TFRC; TRIB2 promotes βTrCP-mediated TFRC ubiquitination and degradation, thereby reducing the labile iron pool. TFRC is required for TRIB2's iron-lowering and anti-ferroptotic effects.","method":"TRIB2 and βTrCP knockout/overexpression in liver cancer cells, ubiquitination assay, labile iron pool measurement, ferroptosis induction assays (RSL3, erastin)","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiments, ubiquitination biochemistry, E3 identification, single lab with multiple orthogonal methods","pmids":["34315867"],"is_preprint":false},{"year":2022,"finding":"CVB3 infection induces nuclear translocation of TFRC (normally a cell membrane protein); transcription factor Sp1 binds the TFRC promoter and upregulates TFRC transcription during CVB3 infection, driving ferroptosis via the Sp1/TFRC/Fe axis.","method":"HeLa cell time-course CVB3 infection model, immunofluorescence for TFRC localization, ChIP for Sp1 binding to TFRC promoter, siRNA knockdown, iron/lipid peroxidation assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, subcellular localization imaging, and functional KD, single lab with multiple methods","pmids":["35821227"],"is_preprint":false},{"year":2020,"finding":"YTHDF1 directly interacts with the 3'UTR and 5'UTR of TFRC mRNA via its methyltransferase domain and positively regulates translation of m6A-modified TFRC mRNA, enhancing iron metabolism in hypopharyngeal squamous cell carcinoma.","method":"m6A-seq, RIP-seq, gain- and loss-of-function analyses, iron metabolic assays, transcriptome sequencing","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP-seq, m6A-seq, functional rescue experiments in a single lab with multiple orthogonal methods","pmids":["33204330"],"is_preprint":false},{"year":2024,"finding":"METTL3 promotes m6A modification of TFRC mRNA; the m6A reader IGF2BP2 recognizes this modification and increases TFRC mRNA stability, enhancing iron uptake and ferroptosis in cardiomyocytes during doxorubicin cardiotoxicity. Cardiomyocyte-specific METTL3 knockout reduces TFRC expression and prevents ferroptosis.","method":"Conditional METTL3 knockout mice, m6A modification assays, RIP for IGF2BP2-TFRC mRNA interaction, ferroptosis markers, in vivo cardiac function assessment","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO mouse model, RIP biochemistry, m6A modification assay, multiple orthogonal readouts, rigorous in vivo and in vitro study","pmids":["38631119"],"is_preprint":false},{"year":2024,"finding":"FTO demethylase targets ACSL4 and TFRC mRNA; FTO inhibits Acsl4 and Tfrc mRNA stability in an m6A-dependent manner, thereby suppressing ferroptosis during ischemia/reperfusion injury in older livers.","method":"Mass spectrometry identification of FTO targets, FTO overexpression in mouse model, m6A mRNA stability assays, ferroptosis markers","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mass spectrometry identification, functional overexpression in vivo, m6A stability assays; single lab","pmids":["38834654"],"is_preprint":false},{"year":2024,"finding":"METTL3 stabilizes NEDD4L mRNA via m6A methylation, enhancing NEDD4L expression. NEDD4L (E3 ubiquitin ligase) ubiquitinates and degrades TFRC, reducing iron accumulation and neuronal ferroptosis after ischemic stroke.","method":"MCAO mouse model, NEDD4L knockout and METTL3 overexpression constructs, co-immunoprecipitation, TFRC half-life/ubiquitination assays, qRT-PCR/western blot","journal":"Cell biology and toxicology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ubiquitination biochemistry, in vivo stroke model, mRNA stability assay; single lab with multiple methods","pmids":["38302612"],"is_preprint":false},{"year":2022,"finding":"ESR1 enhances binding of the E3 ubiquitin ligase NEDD4L to CD71 (TfR1), promoting ubiquitination and degradation of CD71. ESR1 knockdown increases CD71 protein levels and enhances ionizing radiation-induced ferroptosis in breast cancer cells.","method":"Immunoprecipitation, ubiquitination assay, ESR1 knockdown, ferroptosis/lipid peroxidation assays, flow cytometry","journal":"Archives of biochemistry and biophysics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP and ubiquitination biochemistry plus functional KD, single lab with multiple methods","pmids":["35613689"],"is_preprint":false},{"year":2024,"finding":"O-GlcNAcylation of TFRC at serine 687 promotes binding of the ubiquitin E3 ligase MARCH8, leading to polyubiquitination at lysine 665 and TFRC degradation. Erastin-induced de-O-GlcNAcylation of TFRC at Ser687 diminishes MARCH8 binding and decreases TFRC polyubiquitination, thereby stabilizing TFRC and enhancing ferroptosis in HCC cells.","method":"Site-directed mutagenesis (Ser687, Lys665), co-immunoprecipitation, ubiquitination assay, O-GlcNAcylation detection, erastin ferroptosis assays","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mutagenesis of specific PTM sites, Co-IP, ubiquitination biochemistry, functional ferroptosis assays in a single rigorous study","pmids":["38744192"],"is_preprint":false},{"year":2022,"finding":"LC3-dependent EV loading and secretion (LDELS) promotes TFRC secretion via extracellular vesicles. TFRC EV secretion requires MAP1LC3/LC3-conjugation machinery components, multiple ESCRT pathway components, and the small GTPase RAB27A, but is independent of other ATGs involved in classical autophagosome formation.","method":"Genetic knockdown of LC3-conjugation machinery, ESCRT components and RAB27A; EV isolation and proteomic analysis (TMT); functional secretion assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic dissection with multiple pathway components, EV proteomics, single lab","pmids":["36286616"],"is_preprint":false},{"year":2023,"finding":"TFEB overexpression upregulates TfR1 synthesis and increases TfR1 localization to lysosomes, facilitating lysosomal iron import and transient iron storage, maintaining low cellular labile iron. TfR1 knockdown reverses the lower labile iron and upregulation of ferritin chains caused by TFEB overexpression, demonstrating TFEB regulates cellular labile iron in a TfR1-dependent manner.","method":"TFEB overexpression/knockdown, TfR1 knockdown, lysosomal fractionation, labile iron pool measurement, ferritin western blot","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — subcellular fractionation, functional KD rescue experiments, multiple readouts; single lab","pmids":["37683766"],"is_preprint":false},{"year":2023,"finding":"HDAC9 binds HIF-1 and deacetylates it, leading to HIF-1 stabilization (via reduced ubiquitination) and increased TfR1 transcription; simultaneously, HDAC9 binds and deacetylates Sp1, leading to Sp1 ubiquitination and reduced GPX4 expression. Both pathways promote neuronal ferroptosis after ischemia.","method":"ChIP, co-immunoprecipitation, siRNA knockdown of HDAC9/HIF-1/Sp1, OGD/Rx in vitro model, MCAO in vivo model, western blot, ferroptosis marker quantification","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, Co-IP, in vivo and in vitro genetic dissection; single lab with multiple orthogonal methods","pmids":["37324938"],"is_preprint":false},{"year":2023,"finding":"Musclin (a myokine) binds to Tfr1 on beige adipocytes and antagonizes Tfr1-mediated cAMP/PKA-dependent thermogenic induction, thereby attenuating beige fat thermogenesis.","method":"Binding assays, muscle-transgenic and AAV-overexpression mouse models, muscle-specific Musclin knockout mice, cAMP/PKA signaling readouts, thermogenesis measurements","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — binding demonstrated, multiple genetic models (transgenic overexpression and muscle-specific KO), cAMP/PKA signaling dissection, rigorous in vivo study","pmids":["37468484"],"is_preprint":false},{"year":2023,"finding":"Aryl hydrocarbon receptor (Ahr) directly binds to the Tfrc promoter to inhibit transcription, establishing a Ahr-CD71-iron axis that controls ILC3 proliferation. CD71-mediated iron metabolism controls ILC3 mitochondrial respiration by switching oxidative phosphorylation toward glycolysis.","method":"Tfrc conditional ablation in ILC3s, Ahr genetic ablation/activation, ChIP for Ahr binding to Tfrc promoter, metabolic assays (OXPHOS vs glycolysis), infection model (C. rodentium)","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO, ChIP for direct promoter binding, genetic epistasis, metabolic readouts; single rigorous study with multiple orthogonal approaches","pmids":["37709985"],"is_preprint":false},{"year":2024,"finding":"CCT3 interacts with ACTN4, hindering recycling of TFRC to the cell membrane and obstructing iron endocytosis. CCT3 inhibition of ferroptosis depends on deubiquitination of non-degradative K6-linked ubiquitination at CCT3-K21 upon sorafenib treatment.","method":"CRISPR/Cas9 KO library screen, PTM proteomics, Co-IP of CCT3-ACTN4-TFRC, ubiquitination assays, iron endocytosis assays, in vivo xenograft","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, CRISPR screen, ubiquitination biochemistry, functional assays; single lab","pmids":["39210442"],"is_preprint":false},{"year":2025,"finding":"DHHC5 palmitoylates TfR1 at the C98 cysteine site in oligodendrocytes. Neonatal sevoflurane exposure inhibits DHHC5 expression, reducing TfR1 palmitoylation, which enhances TfR1 endocytosis (rather than altering expression level), increases iron uptake and ferroptosis in oligodendrocytes, leading to hypomyelination and cognitive impairment. Specific overexpression of DHHC5 in oligodendrocytes restored TfR1 endocytosis and mitigated these effects.","method":"Acyl-resin assisted capture assay for palmitoylation, Co-IP, single-cell RNA sequencing, Pdgfrα-CreERT conditional mouse model, behavioral tests, iron/ferroptosis markers","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — palmitoylation biochemistry with site identification, conditional mouse model, functional rescue; single lab","pmids":["39929269"],"is_preprint":false},{"year":2024,"finding":"CD36 upregulates TfR1 expression in CD8+ T cells via the oxLDL-p38-CEBPB signaling axis in the tumor microenvironment. Depletion of CD36 in CD8+ T cells inhibits TfR1 upregulation and prevents iron accumulation and lipid peroxidation-driven T cell dysfunction.","method":"Single-cell RNA sequencing, flow cytometry, CD36 depletion, p38/CEBPB inhibitor studies, intracellular iron and lipid peroxide measurements","journal":"Clinical and molecular hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq, genetic depletion, signaling pathway dissection; single lab","pmids":["40037690"],"is_preprint":false},{"year":2024,"finding":"Histone acetyltransferase Kat2a promotes ferroptosis by enhancing H3K27ac and H3K9ac enrichment on the Tfrc (and Hmox1) promoter regions, thereby increasing Tfrc transcription. ALKBH5 demethylase reduces m6A methylation on Kat2a mRNA, and YTHDF2 mediates Kat2a mRNA degradation, providing an upstream regulatory mechanism.","method":"Kat2a inhibition in vitro and in vivo, ChIP for H3K27ac/H3K9ac on Tfrc promoter, YTHDF2/ALKBH5 functional studies, ferroptosis assays in DCM model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for histone marks on specific promoter, functional inhibition, in vivo model; single lab","pmids":["38858351"],"is_preprint":false},{"year":2024,"finding":"ATF3 (activating transcription factor 3) promotes osteocyte ferroptosis during aging by upregulating TfR1 expression (enhancing iron uptake) while simultaneously inhibiting SLC7A11-mediated cystine import, leading to iron overload and lipid peroxidation.","method":"Single-cell transcriptome analysis, ATF3 inhibition in aged mice, ferroptosis markers in cortical bone, TfR1 and SLC7A11 expression analysis","journal":"Cell proliferation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — scRNA-seq identification, in vivo ATF3 inhibition with functional readouts; single lab","pmids":["38764128"],"is_preprint":false},{"year":2024,"finding":"HIF-2α upregulates TFR1 expression in cartilage endplate chondrocytes in response to oxidative stress and pro-inflammatory cytokines; excess TFR1-mediated iron accumulation induces ferroptosis and triggers c-GAS/STING-mediated innate immune inflammation via mitochondrial damage and mtDNA release.","method":"IDD mouse model, TfR1 siRNA knockdown, HIF-2α pathway analysis, c-GAS/STING inhibition with siRNA and ethidium bromide, western blot/immunofluorescence","journal":"Journal of orthopaedic translation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model, pathway dissection via siRNA, functional cGAS/STING rescue; single lab","pmids":["38808263"],"is_preprint":false},{"year":2024,"finding":"TIMP1 regulates HGHF-induced ferroptosis in osteoblasts by inhibiting TFRC ubiquitination (preventing its proteasomal degradation), thereby increasing TFRC protein levels and promoting iron accumulation. TFRC overexpression reversed the ferroptosis inhibition caused by TIMP1 knockout.","method":"TIMP1 knockout and TFRC overexpression in osteoblasts, ubiquitination assays, ferroptosis markers, type 2 diabetic mouse model, western blot/flow cytometry","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination biochemistry, genetic rescue experiment, in vivo diabetic model; single lab","pmids":["39578773"],"is_preprint":false},{"year":2024,"finding":"RAB17 attenuates ferroptosis in endometrial cancer cells by inhibiting TFRC protein expression in a ubiquitin proteasome-dependent manner, thereby reducing iron uptake. Under low-glucose conditions, RAB17 expression increases and limits ferroptosis through the RAB17-TFRC axis.","method":"RAB17 knockdown/overexpression, TFRC protein stability/ubiquitination assays, ferroptosis phenotyping, xenograft and clinical correlation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue, ubiquitination biochemistry, in vivo xenograft; single lab","pmids":["39242574"],"is_preprint":false},{"year":2023,"finding":"NUF2 inhibits p62-mediated autophagic degradation of TFR1 via p38/MAPK signaling, thereby stabilizing TFR1 protein and promoting cholangiocarcinoma progression.","method":"NUF2 overexpression/knockdown, p62-TFR1 binding assay, p38/MAPK inhibition, autophagic flux measurement, TFR1 protein stability assays","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding and degradation assays, signaling pathway inhibition, functional cancer progression readouts; single lab","pmids":["37056930"],"is_preprint":false},{"year":2023,"finding":"ANXA10 knockdown induces ferroptosis by inhibiting autophagy-mediated TFRC degradation, leading to increased TFRC protein levels, labile iron accumulation, and lipid peroxidation in colorectal cancer cells.","method":"ANXA10 knockdown, TFRC protein stability measurement, autophagy flux assay (SQSTM1 accumulation), ferroptosis markers (Fe2+, MDA, ROS), immunofluorescence","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KD, autophagy flux and TFRC stability assays, multiple ferroptosis readouts; single lab","pmids":["37666806"],"is_preprint":false},{"year":2019,"finding":"TfR1 is identified as the cell-surface target of the aptamer XQ-2d on pancreatic cancer cells. XQ-2d shares the same binding site on CD71 as transferrin (Tf), competitively inhibiting Tf binding, while the anti-CD71 antibody binds at a distinct site approximately 15 nm away as measured by surface energy transfer nanoruler.","method":"CD71 knockdown abolishing aptamer binding, competitive binding analysis with Tf and anti-CD71 antibody, surface energy transfer (SET) nanoruler distance measurement, molecular dynamics simulation","journal":"Journal of the American Chemical Society","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding site identified by competition assay and distance measurement, genetic knockdown confirmation; single lab","pmids":["31185171"],"is_preprint":false},{"year":2009,"finding":"TFRC is an immediate target gene of the canonical Wnt pathway, with Myc and Tfrc expression induced within less than 1 hour of Wnt-3a stimulation in C57MG cells, earlier than other Wnt targets such as Ccnd1.","method":"Time-course gene expression analysis after Wnt-3a stimulation, classification of target gene expression chronology","journal":"Cell biology international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single expression time-course, no mechanistic dissection of how Wnt directly controls TFRC transcription","pmids":["19353769"],"is_preprint":false},{"year":2009,"finding":"miR-320 targets the transferrin receptor 1 (TfR1/CD71) 3'UTR and suppresses TfR1 surface expression and cell proliferation in HL-60 leukemia cells during monocytic differentiation.","method":"miR-320 enforced expression in HL-60 cells, TfR1 surface expression measurement, cell proliferation assay","journal":"Experimental hematology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single cell line, single method for target validation (expression), no direct luciferase 3'UTR reporter shown in abstract","pmids":["19135902"],"is_preprint":false},{"year":2020,"finding":"TFRC is essential for meiotic progression in mouse spermatocytes; TFRC knockdown via morpholino causes spermatocyte apoptosis, accumulation of leptotene/zygotene spermatocytes, arrest before pachytene, sustained γH2AX association, and SYCP1/SYCP3 dissociation beyond the sex body, indicating roles in DNA double-strand break repair and chromosomal synapsis.","method":"TFRC knockdown via morpholino oligonucleotides in neonatal testis culture, chromosomal spread technique, γH2AX/SYCP1/SYCP3 immunostaining, apoptosis assay","journal":"Zygote","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino KD with defined meiotic phenotype, chromosomal spread with molecular markers; single lab","pmids":["33323153"],"is_preprint":false},{"year":2024,"finding":"NAT10-mediated ac4C acetylation of TFRC mRNA stabilizes it, increasing TFRC expression and promoting ferroptosis in lung microvascular endothelial cells during sepsis-induced pulmonary injury.","method":"NAT10 inhibition in vitro and in vivo (sepsis rat model), ac4C assay on TFRC mRNA, ferroptosis markers, cell viability assays","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ac4C modification assay on specific mRNA target, in vivo model, functional rescue; single lab","pmids":["39251905"],"is_preprint":false},{"year":2023,"finding":"TFEB promotes TFRC in cardiomyocytes via STAT3, which in turn upregulates Ccl2 expression to recruit and activate macrophages. HIF-1α regulates TFRC expression in cardiomyocytes during heart failure.","method":"TAC mouse model, ISO/PHE-stimulated cardiomyocytes, immunofluorescence for TFRC and macrophage infiltration, flow cytometry, STAT3 pathway analysis, HIF-1α manipulation","journal":"Immunity, inflammation and disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional cell signaling data present but mechanistic link between TFRC and STAT3-Ccl2 is inferential with limited biochemistry shown in abstract","pmids":["37647427"],"is_preprint":false},{"year":2019,"finding":"lncRNA-IUR-5 suppresses Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71 (TfR1), as demonstrated by RNA pulldown and RNA immunoprecipitation showing lncRNA-IUR-5 interaction with STAT5 pathway components.","method":"RNA pulldown, RNA immunoprecipitation (RIP), transcriptome RNA-seq, lncRNA-IUR KD transgenic mice, Bcr-Abl transformation assay","journal":"Molecular cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — RIP shows interaction but mechanistic link between lncRNA-IUR-5 and STAT5-CD71 is not fully biochemically resolved in abstract","pmids":["30961617"],"is_preprint":false},{"year":2024,"finding":"FTO demethylase activity reduces m6A modification on TfRc mRNA; YTHDF1 binds m6A-modified TfRc mRNA and promotes its translation, while YTHDF2 mediates stability of SLC7A11 mRNA via m6A. Inhibition of AR transcriptional regulation of FTO by BPF exposure dysregulates this axis.","method":"ChIP for AR binding to FTO promoter, MeRIP for m6A on TfRc mRNA, RIP for YTHDF1-TfRc mRNA and YTHDF2-SLC7A11 mRNA binding, FTO overexpression","journal":"Environmental pollution","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP and RIP biochemistry establishing m6A modification and reader binding to TFRC mRNA; single lab","pmids":["38996995"],"is_preprint":false},{"year":2024,"finding":"Serum iron, transferrin saturation, and hepatic Tfrc expression exhibit circadian rhythms that are maintained in constant darkness and ablated by Bmal1 knockout, demonstrating endogenous circadian control. Hepatic Tfrc expression and erythropoietic activity oscillate in opposing phases.","method":"Constant darkness housing, Bmal1 knockout mice, time-series serum iron and TSAT measurement, hepatic Tfrc qPCR, erythropoietic activity assays","journal":"American journal of hematology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic disruption of circadian machinery (Bmal1 KO) abolishes Tfrc oscillation, constant darkness control; single lab","pmids":["39152780"],"is_preprint":false},{"year":2023,"finding":"H3K9me3 (mediated by Suv39h1 methyltransferase) is enriched at the promoter and gene body of Tfr1 and represses its transcription during hemin-induced ferroptosis in neuronal cells. Inhibition of Suv39h1/H3K9me3 aggravates ferroptosis by upregulating Tfr1 expression, demonstrating a protective epigenetic mechanism.","method":"ChIP for H3K9me3 at Tfr1 promoter, Suv39h1 siRNA/inhibitor, hemin/RSL3 ferroptosis model, Tfr1 expression analysis, in vivo ICH mouse model with intracerebroventricular Suv39h1 siRNA","journal":"Journal of cerebral blood flow and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP at specific promoter, genetic and pharmacological inhibition in vitro and in vivo; single lab","pmids":["36960698"],"is_preprint":false},{"year":2024,"finding":"TfR1 in CD71+ regulatory T cells (Tregs) is required for Treg perinatal expansion. Treg-restricted CD71 deficiency leads to a scurfy-like autoimmune disease, impaired perinatal Treg proliferation, loss of tissue-Treg gene signature, and hepatic iron overload with increased hepcidin. CD71-null Tregs show decreased proliferation.","method":"Treg-specific conditional CD71 knockout mice, Treg proliferation assays, tissue-Treg gene signature analysis, iron metabolism measurements, hepcidin quantification, fecal microbiota analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell type-specific conditional KO with multiple defined phenotypes (autoimmunity, proliferation, iron homeostasis); rigorous in vivo model","pmids":["38954474"],"is_preprint":false},{"year":2024,"finding":"TfR1 knockdown in neural cells differentiated from Alzheimer's disease patient-derived iPSCs reduces iron overload and mitochondrial dysfunction. TfR1 interacts with GSK3B and promotes GSK3B expression; GSK3B overexpression reverses the protective effects of TfR1 knockdown.","method":"TfR1 knockdown/overexpression in AD-iPS differentiated neural cells, co-immunoprecipitation for TfR1-GSK3B interaction, iron/ROS/mitochondrial membrane potential assays, GSK3B rescue experiment","journal":"European journal of medical research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for TfR1-GSK3B, genetic rescue experiments, multiple functional readouts; single lab","pmids":["38321571"],"is_preprint":false},{"year":2023,"finding":"Complement C4 directly interacts with TFRC during CVB3 infection (identified by Co-IP and mass spectrometry), and this interaction leads to increased C4b production and decreased downstream complement C3. Regulating the complement C4/C3 pathway via TFRC modulates ferroptosis in CVB3-infected cardiomyocytes.","method":"Co-IP and protein mass spectrometry for TFRC-interacting proteins, Fer-1 treatment, complement C3/C4b quantification, functional ferroptosis assays","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mass spectrometry identification of C4 as TFRC binding partner, functional downstream assays; single lab","pmids":["38169212"],"is_preprint":false}],"current_model":"TFRC (TfR1/CD71) is a type II transmembrane homodimeric glycoprotein that mediates cellular iron uptake by binding transferrin-bound iron and undergoing clathrin-mediated endocytosis via a tyrosine-based internalization motif (Tyr20); its activity, stability, and trafficking are regulated by multiple post-translational modifications including stearoylation (inhibiting JNK activation and promoting mitochondrial fusion via HUWE1/mitofusin), O-GlcNAcylation (at Ser687, controlling MARCH8-mediated ubiquitination at Lys665), palmitoylation by DHHC5 (at Cys98, controlling endocytosis rate in oligodendrocytes), and ubiquitin-mediated proteasomal degradation via NEDD4L, βTrCP, or MARCH8; its mRNA is regulated post-transcriptionally by m6A methylation (written by METTL3, read by IGF2BP2 for stabilization or YTHDF1 for translation, demethylated by FTO) and ac4C modification (by NAT10), and transcriptionally by HIF-1, HIF-2α, Sp1, ATF3, STAT5, Ahr, and the Wnt pathway; TfR1 also physically interacts with HFE in hepatocytes to regulate hepcidin production and systemic iron homeostasis, with STEAP3 to provide an accessory endocytosis signal in erythroblasts, with the IKK complex to support NF-κB signaling, with GSK3B to modulate neuronal iron metabolism, with complement C4 during viral infection, and with Musclin to transduce a thermogenic signaling pathway via cAMP/PKA; loss of TfR1 function in lymphocytes (due to internalization-defective mutations) causes combined immunodeficiency by impairing iron-dependent lymphocyte activation, while in erythroid precursors TfR1 overexpression drives ineffective erythropoiesis in β-thalassemia, and in various cell types excess TfR1-mediated iron uptake promotes ferroptosis through labile iron pool expansion and lipid peroxidation."},"narrative":{"mechanistic_narrative":"TFRC (TfR1/CD71) is the principal cell-surface receptor for transferrin-bound iron uptake, and the depth of its post-translational, transcriptional, and trafficking regulation positions it as a central control node for cellular labile iron and, consequently, for ferroptosis [PMID:26642240, PMID:37683766]. Receptor internalization depends on an intact tyrosine-based motif: a homozygous p.Tyr20His substitution disrupts endocytosis, raises surface TfR1, impairs transferrin uptake, and causes a combined immunodeficiency that is rescued by iron citrate and by wild-type but not mutant TfR1, establishing iron-dependent lymphocyte activation as a nonredundant TfR1 function [PMID:26642240]. Beyond constitutive iron import, TfR1 abundance and activity are tuned by multiple modifications—stearoylation that restrains JNK signaling and promotes mitochondrial fusion via HUWE1/mitofusin [PMID:26214738], O-GlcNAcylation at Ser687 that licenses MARCH8 binding and Lys665 polyubiquitination [PMID:38744192], and DHHC5-mediated palmitoylation at Cys98 that sets endocytosis rate in oligodendrocytes [PMID:39929269]. Protein levels are further set by ubiquitin-dependent degradation through NEDD4L and βTrCP and by autophagic turnover, with multiple E3 ligases and adaptors converging on TfR1 to lower the labile iron pool and suppress ferroptosis [PMID:34315867, PMID:38302612, PMID:35613689, PMID:38744192]. TFRC mRNA is regulated by m6A methylation (METTL3 writing, IGF2BP2 stabilizing, YTHDF1 enhancing translation, FTO demethylating) and by NAT10-dependent ac4C acetylation, while its transcription is driven by HIF-1/HIF-2α, Sp1, ATF3, and Ahr and is restrained by repressive H3K9me3 chromatin [PMID:38631119, PMID:38834654, PMID:33204330, PMID:39251905, PMID:37324938, PMID:38808263, PMID:35821227, PMID:37709985, PMID:36960698]. Through these inputs, excess TfR1-mediated iron import drives ferroptosis across diverse tissues, whereas physiological TfR1 also supports systemic iron homeostasis via an HFE-dependent hepatocyte function controlling hepcidin, contributes to ineffective erythropoiesis in β-thalassemia, and supports regulatory T cell and ILC3 expansion and metabolic programming [PMID:36322932, PMID:28151426, PMID:38954474, PMID:37709985]. TfR1 additionally engages non-canonical partners—the IKK complex to sustain NF-κB signaling and the myokine Musclin to gate cAMP/PKA-dependent adipocyte thermogenesis [PMID:23016877, PMID:37468484].","teleology":[{"year":2009,"claim":"Early work placed TFRC expression downstream of growth and developmental signaling, framing it as an inducible rather than purely housekeeping gene.","evidence":"Wnt-3a stimulation time-course in C57MG cells; miR-320 enforced expression in HL-60 cells","pmids":["19353769","19135902"],"confidence":"Low","gaps":["Wnt linkage is correlative time-course with no direct promoter mechanism","miR-320 target validation lacks a direct 3'UTR reporter"]},{"year":2013,"claim":"Established that TfR1 has a signaling role beyond iron import by physically scaffolding the IKK complex to sustain NF-κB-dependent transcription and protect against TNFα-induced apoptosis.","evidence":"Unbiased proteomics, reciprocal Co-IP, siRNA knockdown, NF-κB reporter and chromatin binding assays","pmids":["23016877"],"confidence":"Medium","gaps":["Structural basis of TfR1-IKK contact unresolved","Whether iron import is required for the NF-κB effect not separated"]},{"year":2015,"claim":"Defined the genetic and structural requirement for TfR1 endocytosis in human disease, showing that a Tyr20 motif mutation causes combined immunodeficiency through defective receptor internalization rescuable by iron.","evidence":"Patient fibroblast rescue, Tfrc(Y20H/Y20H) knock-in mice, endocytosis assays, STEAP3 Co-IP","pmids":["26642240"],"confidence":"High","gaps":["STEAP3 accessory endocytosis signal only partially defined","Tissue specificity of the immune phenotype not fully explained"]},{"year":2015,"claim":"Revealed a lipid-modification arm of TfR1 regulation in which stearoylation suppresses TfR1-driven JNK signaling and promotes mitochondrial fusion, linking dietary fatty acids to mitochondrial dynamics.","evidence":"In vivo dietary C18:0 manipulation, Drosophila genetics, stearoylation biochemistry, mitofusin ubiquitination assay","pmids":["26214738"],"confidence":"High","gaps":["Stearoylation site on TfR1 not mapped here","Connection between stearoylation and canonical iron uptake unaddressed"]},{"year":2017,"claim":"Demonstrated that TfR1 dosage in erythroid precursors drives ineffective erythropoiesis, with haploinsufficiency correcting iron overload in β-thalassemia.","evidence":"TfR1+/- × β-thalassemia mouse crosses, erythroid culture with apotransferrin, flow cytometry, in vivo iron measures","pmids":["28151426"],"confidence":"High","gaps":["Mechanism of apotransferrin suppression of TfR1 not molecularly defined","Human translatability not tested"]},{"year":2023,"claim":"Showed that hepatocyte TfR1's role in systemic iron homeostasis and hepcidin regulation is strictly HFE-dependent, resolving the in vivo partnership controlling iron sensing.","evidence":"Hepatocyte-specific Tfrc knockout, Tfrc/Hfe double knockout epistasis, β-thalassemia model, iron and hepcidin quantification","pmids":["36322932"],"confidence":"High","gaps":["Molecular details of TfR1-HFE-mediated hepcidin signaling not dissected here","Other hepatic iron sensors not excluded"]},{"year":2023,"claim":"Extended TfR1 function into immune and metabolic programming, establishing transcriptional repression by Ahr controls ILC3 iron metabolism and a Musclin-TfR1 axis that gates adipocyte thermogenesis.","evidence":"Tfrc conditional ablation in ILC3, Ahr ChIP and genetic ablation, metabolic assays; Musclin binding and muscle-specific KO mice with cAMP/PKA readouts","pmids":["37709985","37468484"],"confidence":"High","gaps":["Whether Musclin and transferrin compete for TfR1 not defined","How iron flux couples to OXPHOS-glycolysis switch mechanistically open"]},{"year":2024,"claim":"Defined a Treg-intrinsic requirement for TfR1, showing iron uptake supports perinatal Treg expansion and prevents scurfy-like autoimmunity.","evidence":"Treg-specific conditional CD71 knockout, proliferation and tissue-Treg signature analysis, iron and hepcidin measurements","pmids":["38954474"],"confidence":"High","gaps":["Iron-dependent metabolic targets in Tregs not identified","Link between Treg iron and systemic hepcidin not fully mechanistic"]},{"year":2024,"claim":"Mapped a multilayered code controlling TfR1 protein stability through site-specific O-GlcNAcylation and competing E3 ligase pathways that set the labile iron pool and ferroptosis sensitivity.","evidence":"Ser687/Lys665 mutagenesis, MARCH8 Co-IP and ubiquitination assays; NEDD4L, βTrCP, ESR1, TIMP1, RAB17 ubiquitination/stability studies across cancer and injury models","pmids":["38744192","38302612","34315867","35613689","39578773","39242574"],"confidence":"High","gaps":["Hierarchy among competing E3 ligases in a single cell type unresolved","Crosstalk between O-GlcNAc, palmitoylation, and ubiquitination not integrated"]},{"year":2024,"claim":"Established RNA-level control of TFRC by m6A and ac4C, identifying writers, readers, and erasers that tune TFRC stability and translation to drive or restrain ferroptosis in vivo.","evidence":"METTL3 conditional KO, IGF2BP2/YTHDF1 RIP, FTO target identification, NAT10 ac4C assays across cardiac, hepatic, and pulmonary injury models","pmids":["38631119","33204330","38834654","39251905","38996995"],"confidence":"High","gaps":["Relative contribution of stabilization versus translational control unclear","Whether multiple RNA modifications act on the same transcripts simultaneously untested"]},{"year":2024,"claim":"Detailed transcriptional and chromatin control converging on the Tfrc promoter, with HIF-1/HIF-2α, Sp1, ATF3, and Kat2a-driven acetylation activating, and Suv39h1/H3K9me3 repressing, transcription to set ferroptosis thresholds.","evidence":"ChIP for transcription factors and histone marks, HDAC9/HIF/Sp1 dissection, Kat2a and Suv39h1 manipulation in ischemia and cardiomyopathy models","pmids":["37324938","38858351","38764128","38808263","35821227","36960698"],"confidence":"Medium","gaps":["Combinatorial logic of these factors at the promoter not resolved","Cell-type specificity of repressive versus activating control unclear"]},{"year":2024,"claim":"Uncovered trafficking and non-iron interactions of TfR1, including palmitoylation-controlled endocytosis, CCT3/ACTN4-dependent recycling, autophagic and EV-mediated turnover, and partnerships with GSK3B and complement C4.","evidence":"DHHC5 palmitoylation site mapping in oligodendrocytes, CCT3-ACTN4-TFRC Co-IP, LDELS/ESCRT/RAB27A EV secretion dissection, GSK3B and C4 Co-IP","pmids":["39929269","39210442","36286616","38321571","38169212"],"confidence":"Medium","gaps":["Functional significance of TfR1 EV secretion unknown","TfR1-GSK3B and TfR1-C4 interactions rest on single-lab Co-IP"]},{"year":null,"claim":"How the numerous parallel regulatory layers — PTMs, competing E3 ligases, RNA modifications, transcription factors, and trafficking machinery — are integrated within a single cell to set TfR1 surface density and iron flux remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unified model reconciling competing degradation and stabilization pathways","Quantitative contribution of each layer to net iron uptake unmeasured","Structural basis for most non-transferrin partner interactions undetermined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,28]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[0,14]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[2,16]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6,28]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,13]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[14]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[6]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,4,14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[5,8,12,23]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[2,17,38]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,16,36]}],"complexes":[],"partners":["HFE","STEAP3","IKK","MARCH8","NEDD4L","GSK3B","MUSCLIN","C4"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P02786","full_name":"Transferrin receptor protein 1","aliases":["T9","Transferrin receptor 1","p90"],"length_aa":760,"mass_kda":84.9,"function":"Cellular uptake of iron occurs via receptor-mediated endocytosis of ligand-occupied transferrin receptor into specialized endosomes (PubMed:26214738). Endosomal acidification leads to iron release. The apotransferrin-receptor complex is then recycled to the cell surface with a return to neutral pH and the concomitant loss of affinity of apotransferrin for its receptor. Transferrin receptor is necessary for development of erythrocytes and the nervous system (By similarity). A second ligand, the hereditary hemochromatosis protein HFE, competes for binding with transferrin for an overlapping C-terminal binding site. Positively regulates T and B cell proliferation through iron uptake (PubMed:26642240). Acts as a lipid sensor that regulates mitochondrial fusion by regulating activation of the JNK pathway (PubMed:26214738). When dietary levels of stearate (C18:0) are low, promotes activation of the JNK pathway, resulting in HUWE1-mediated ubiquitination and subsequent degradation of the mitofusin MFN2 and inhibition of mitochondrial fusion (PubMed:26214738). When dietary levels of stearate (C18:0) are high, TFRC stearoylation inhibits activation of the JNK pathway and thus degradation of the mitofusin MFN2 (PubMed:26214738). Mediates uptake of NICOL1 into fibroblasts where it may regulate extracellular matrix production (By similarity) (Microbial infection) Acts as a receptor for new-world arenaviruses: Guanarito, Junin and Machupo virus (Microbial infection) Acts as a host entry factor for rabies virus that hijacks the endocytosis of TFRC to enter cells (Microbial infection) Acts as a host entry factor for SARS-CoV, MERS-CoV and SARS-CoV-2 viruses that hijack the endocytosis of TFRC to enter cells (Microbial infection) Acts as a receptor for Plasmodium vivax","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/P02786/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/TFRC","classification":"Common Essential","n_dependent_lines":890,"n_total_lines":1208,"dependency_fraction":0.7367549668874173},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000072274","cell_line_id":"CID000882","localizations":[{"compartment":"membrane","grade":3},{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"ATP6AP2","stoichiometry":10.0},{"gene":"RAB11A","stoichiometry":10.0},{"gene":"SCAMP2","stoichiometry":10.0},{"gene":"VAMP3","stoichiometry":4.0},{"gene":"ARHGAP18","stoichiometry":0.2},{"gene":"CALD1","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"LAMP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000882","total_profiled":1310},"omim":[{"mim_id":"621025","title":"RAB3A-INTERACTING PROTEIN-LIKE 1; RAB3IL1","url":"https://www.omim.org/entry/621025"},{"mim_id":"620229","title":"FHF COMPLEX SUBUNIT HOOK-INTERACTING PROTEIN 1B; FHIP1B","url":"https://www.omim.org/entry/620229"},{"mim_id":"619811","title":"UHRF1-BINDING PROTEIN 1-LIKE; UHRF1BP1L","url":"https://www.omim.org/entry/619811"},{"mim_id":"619685","title":"NEURODEVELOPMENTAL DISORDER WITH MICROCEPHALY, SEIZURES, AND NEONATAL CHOLESTASIS; NEDMSC","url":"https://www.omim.org/entry/619685"},{"mim_id":"619273","title":"CIMDAG SYNDROME; CIMDAG","url":"https://www.omim.org/entry/619273"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endosomes","reliability":"Supported"},{"location":"Lysosomes","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TFRC"},"hgnc":{"alias_symbol":["CD71","TFR1","p90"],"prev_symbol":[]},"alphafold":{"accession":"P02786","domains":[{"cath_id":"3.40.630.10","chopping":"125-191_384-604","consensus_level":"high","plddt":96.2998,"start":125,"end":604},{"cath_id":"3.50.30.30","chopping":"200-379","consensus_level":"high","plddt":92.7053,"start":200,"end":379},{"cath_id":"1.20.930.40","chopping":"613-756","consensus_level":"high","plddt":92.6027,"start":613,"end":756}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P02786","model_url":"https://alphafold.ebi.ac.uk/files/AF-P02786-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P02786-F1-predicted_aligned_error_v6.png","plddt_mean":86.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TFRC","jax_strain_url":"https://www.jax.org/strain/search?query=TFRC"},"sequence":{"accession":"P02786","fasta_url":"https://rest.uniprot.org/uniprotkb/P02786.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P02786/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P02786"}},"corpus_meta":[{"pmid":"32827544","id":"PMC_32827544","title":"LncRNA 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STEAP3, a metalloreductase expressed in erythroblasts, was shown to associate with TfR1 and partially rescue transferrin uptake, suggesting an accessory endocytosis signal.\",\n      \"method\": \"Patient-derived fibroblast rescue assay, Co-IP, Tfrc(Y20H/Y20H) knock-in mouse model, endocytosis assays\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (patient cells, mouse model, rescue with WT vs mutant, Co-IP for STEAP3 interaction), single rigorous study with strong controls\",\n      \"pmids\": [\"26642240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Stearic acid (C18:0) stearoylates TfR1 (TFRC), thereby inhibiting TfR1-mediated activation of JNK signaling. This reduces ubiquitination of mitofusin via HUWE1, promoting mitochondrial fusion and function. Dietary C18:0 intake modulates this pathway in vivo.\",\n      \"method\": \"In vivo dietary manipulation, Drosophila genetic model, biochemical stearoylation assay, JNK signaling readouts, mitofusin ubiquitination assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — pathway dissected with multiple orthogonal methods (biochemistry, genetics, in vivo dietary intervention), published in high-quality journal with rigorous controls\",\n      \"pmids\": [\"26214738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TfR1 physically interacts with the IKK complex. TfR1 depletion reduces IKK complex formation and inhibits TNFα-induced NF-κB-dependent transcription; NF-κB fails to translocate to the nucleus efficiently, reducing target gene promoter binding and increasing apoptosis in response to TNFα.\",\n      \"method\": \"Unbiased proteomics screen, Co-IP, siRNA knockdown, NF-κB reporter assay, chromatin binding assay, apoptosis assay\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus functional readouts (NF-κB nuclear translocation, promoter binding, apoptosis), single lab with multiple orthogonal methods\",\n      \"pmids\": [\"23016877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Overexpression of TfR1 in β-thalassemic erythroid precursors contributes to ineffective erythropoiesis and iron overload. Apotransferrin inhibits TfR1 expression independently of erythropoietin and iron-related signaling, decreases TfR1 partitioning to reticulocytes during enucleation, and enhances enucleation. Haploinsufficiency of TfR1 (TfR1+/-) crossed into β-thalassemic mice reverses iron overload and improves hepcidin derepression.\",\n      \"method\": \"Mouse genetic crosses (TfR1+/- × β-thalassemia), in vitro erythroid culture with apotransferrin, flow cytometry, in vivo iron measurements\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model combined with in vitro mechanistic dissection, multiple orthogonal endpoints, replicated across conditions\",\n      \"pmids\": [\"28151426\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Hepatocyte TfR1 interacts with HFE to regulate hepcidin production. Hepatocyte-specific Tfrc knockout in mice leads to reduced serum/liver iron and inappropriately elevated hepcidin relative to iron status, but ablation of hepatocyte Tfrc has no impact on iron phenotype in Hfe knockout mice, demonstrating that TfR1's nonredundant function in systemic iron homeostasis depends on HFE. Ablation of hepatocyte Tfrc in β-thalassemia mice ameliorates hepcidin deficiency and liver iron loading.\",\n      \"method\": \"Hepatocyte-specific conditional Tfrc knockout mice (Tfrcfl/fl;Alb-Cre+), double knockout with Hfe, β-thalassemia mouse model, serum/liver iron measurements, hepcidin quantification\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout genetics with multiple disease models and epistasis analysis, rigorous in vivo study\",\n      \"pmids\": [\"36322932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIB2 desensitizes cells to ferroptosis via the E3 ubiquitin ligase βTrCP, which ubiquitinates TFRC; TRIB2 promotes βTrCP-mediated TFRC ubiquitination and degradation, thereby reducing the labile iron pool. TFRC is required for TRIB2's iron-lowering and anti-ferroptotic effects.\",\n      \"method\": \"TRIB2 and βTrCP knockout/overexpression in liver cancer cells, ubiquitination assay, labile iron pool measurement, ferroptosis induction assays (RSL3, erastin)\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiments, ubiquitination biochemistry, E3 identification, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"34315867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CVB3 infection induces nuclear translocation of TFRC (normally a cell membrane protein); transcription factor Sp1 binds the TFRC promoter and upregulates TFRC transcription during CVB3 infection, driving ferroptosis via the Sp1/TFRC/Fe axis.\",\n      \"method\": \"HeLa cell time-course CVB3 infection model, immunofluorescence for TFRC localization, ChIP for Sp1 binding to TFRC promoter, siRNA knockdown, iron/lipid peroxidation assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, subcellular localization imaging, and functional KD, single lab with multiple methods\",\n      \"pmids\": [\"35821227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"YTHDF1 directly interacts with the 3'UTR and 5'UTR of TFRC mRNA via its methyltransferase domain and positively regulates translation of m6A-modified TFRC mRNA, enhancing iron metabolism in hypopharyngeal squamous cell carcinoma.\",\n      \"method\": \"m6A-seq, RIP-seq, gain- and loss-of-function analyses, iron metabolic assays, transcriptome sequencing\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP-seq, m6A-seq, functional rescue experiments in a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33204330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL3 promotes m6A modification of TFRC mRNA; the m6A reader IGF2BP2 recognizes this modification and increases TFRC mRNA stability, enhancing iron uptake and ferroptosis in cardiomyocytes during doxorubicin cardiotoxicity. Cardiomyocyte-specific METTL3 knockout reduces TFRC expression and prevents ferroptosis.\",\n      \"method\": \"Conditional METTL3 knockout mice, m6A modification assays, RIP for IGF2BP2-TFRC mRNA interaction, ferroptosis markers, in vivo cardiac function assessment\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO mouse model, RIP biochemistry, m6A modification assay, multiple orthogonal readouts, rigorous in vivo and in vitro study\",\n      \"pmids\": [\"38631119\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTO demethylase targets ACSL4 and TFRC mRNA; FTO inhibits Acsl4 and Tfrc mRNA stability in an m6A-dependent manner, thereby suppressing ferroptosis during ischemia/reperfusion injury in older livers.\",\n      \"method\": \"Mass spectrometry identification of FTO targets, FTO overexpression in mouse model, m6A mRNA stability assays, ferroptosis markers\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mass spectrometry identification, functional overexpression in vivo, m6A stability assays; single lab\",\n      \"pmids\": [\"38834654\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL3 stabilizes NEDD4L mRNA via m6A methylation, enhancing NEDD4L expression. NEDD4L (E3 ubiquitin ligase) ubiquitinates and degrades TFRC, reducing iron accumulation and neuronal ferroptosis after ischemic stroke.\",\n      \"method\": \"MCAO mouse model, NEDD4L knockout and METTL3 overexpression constructs, co-immunoprecipitation, TFRC half-life/ubiquitination assays, qRT-PCR/western blot\",\n      \"journal\": \"Cell biology and toxicology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ubiquitination biochemistry, in vivo stroke model, mRNA stability assay; single lab with multiple methods\",\n      \"pmids\": [\"38302612\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ESR1 enhances binding of the E3 ubiquitin ligase NEDD4L to CD71 (TfR1), promoting ubiquitination and degradation of CD71. ESR1 knockdown increases CD71 protein levels and enhances ionizing radiation-induced ferroptosis in breast cancer cells.\",\n      \"method\": \"Immunoprecipitation, ubiquitination assay, ESR1 knockdown, ferroptosis/lipid peroxidation assays, flow cytometry\",\n      \"journal\": \"Archives of biochemistry and biophysics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP and ubiquitination biochemistry plus functional KD, single lab with multiple methods\",\n      \"pmids\": [\"35613689\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"O-GlcNAcylation of TFRC at serine 687 promotes binding of the ubiquitin E3 ligase MARCH8, leading to polyubiquitination at lysine 665 and TFRC degradation. Erastin-induced de-O-GlcNAcylation of TFRC at Ser687 diminishes MARCH8 binding and decreases TFRC polyubiquitination, thereby stabilizing TFRC and enhancing ferroptosis in HCC cells.\",\n      \"method\": \"Site-directed mutagenesis (Ser687, Lys665), co-immunoprecipitation, ubiquitination assay, O-GlcNAcylation detection, erastin ferroptosis assays\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mutagenesis of specific PTM sites, Co-IP, ubiquitination biochemistry, functional ferroptosis assays in a single rigorous study\",\n      \"pmids\": [\"38744192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LC3-dependent EV loading and secretion (LDELS) promotes TFRC secretion via extracellular vesicles. TFRC EV secretion requires MAP1LC3/LC3-conjugation machinery components, multiple ESCRT pathway components, and the small GTPase RAB27A, but is independent of other ATGs involved in classical autophagosome formation.\",\n      \"method\": \"Genetic knockdown of LC3-conjugation machinery, ESCRT components and RAB27A; EV isolation and proteomic analysis (TMT); functional secretion assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic dissection with multiple pathway components, EV proteomics, single lab\",\n      \"pmids\": [\"36286616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TFEB overexpression upregulates TfR1 synthesis and increases TfR1 localization to lysosomes, facilitating lysosomal iron import and transient iron storage, maintaining low cellular labile iron. TfR1 knockdown reverses the lower labile iron and upregulation of ferritin chains caused by TFEB overexpression, demonstrating TFEB regulates cellular labile iron in a TfR1-dependent manner.\",\n      \"method\": \"TFEB overexpression/knockdown, TfR1 knockdown, lysosomal fractionation, labile iron pool measurement, ferritin western blot\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — subcellular fractionation, functional KD rescue experiments, multiple readouts; single lab\",\n      \"pmids\": [\"37683766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"HDAC9 binds HIF-1 and deacetylates it, leading to HIF-1 stabilization (via reduced ubiquitination) and increased TfR1 transcription; simultaneously, HDAC9 binds and deacetylates Sp1, leading to Sp1 ubiquitination and reduced GPX4 expression. Both pathways promote neuronal ferroptosis after ischemia.\",\n      \"method\": \"ChIP, co-immunoprecipitation, siRNA knockdown of HDAC9/HIF-1/Sp1, OGD/Rx in vitro model, MCAO in vivo model, western blot, ferroptosis marker quantification\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, Co-IP, in vivo and in vitro genetic dissection; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37324938\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Musclin (a myokine) binds to Tfr1 on beige adipocytes and antagonizes Tfr1-mediated cAMP/PKA-dependent thermogenic induction, thereby attenuating beige fat thermogenesis.\",\n      \"method\": \"Binding assays, muscle-transgenic and AAV-overexpression mouse models, muscle-specific Musclin knockout mice, cAMP/PKA signaling readouts, thermogenesis measurements\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — binding demonstrated, multiple genetic models (transgenic overexpression and muscle-specific KO), cAMP/PKA signaling dissection, rigorous in vivo study\",\n      \"pmids\": [\"37468484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Aryl hydrocarbon receptor (Ahr) directly binds to the Tfrc promoter to inhibit transcription, establishing a Ahr-CD71-iron axis that controls ILC3 proliferation. CD71-mediated iron metabolism controls ILC3 mitochondrial respiration by switching oxidative phosphorylation toward glycolysis.\",\n      \"method\": \"Tfrc conditional ablation in ILC3s, Ahr genetic ablation/activation, ChIP for Ahr binding to Tfrc promoter, metabolic assays (OXPHOS vs glycolysis), infection model (C. rodentium)\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO, ChIP for direct promoter binding, genetic epistasis, metabolic readouts; single rigorous study with multiple orthogonal approaches\",\n      \"pmids\": [\"37709985\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCT3 interacts with ACTN4, hindering recycling of TFRC to the cell membrane and obstructing iron endocytosis. CCT3 inhibition of ferroptosis depends on deubiquitination of non-degradative K6-linked ubiquitination at CCT3-K21 upon sorafenib treatment.\",\n      \"method\": \"CRISPR/Cas9 KO library screen, PTM proteomics, Co-IP of CCT3-ACTN4-TFRC, ubiquitination assays, iron endocytosis assays, in vivo xenograft\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, CRISPR screen, ubiquitination biochemistry, functional assays; single lab\",\n      \"pmids\": [\"39210442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DHHC5 palmitoylates TfR1 at the C98 cysteine site in oligodendrocytes. Neonatal sevoflurane exposure inhibits DHHC5 expression, reducing TfR1 palmitoylation, which enhances TfR1 endocytosis (rather than altering expression level), increases iron uptake and ferroptosis in oligodendrocytes, leading to hypomyelination and cognitive impairment. Specific overexpression of DHHC5 in oligodendrocytes restored TfR1 endocytosis and mitigated these effects.\",\n      \"method\": \"Acyl-resin assisted capture assay for palmitoylation, Co-IP, single-cell RNA sequencing, Pdgfrα-CreERT conditional mouse model, behavioral tests, iron/ferroptosis markers\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — palmitoylation biochemistry with site identification, conditional mouse model, functional rescue; single lab\",\n      \"pmids\": [\"39929269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CD36 upregulates TfR1 expression in CD8+ T cells via the oxLDL-p38-CEBPB signaling axis in the tumor microenvironment. Depletion of CD36 in CD8+ T cells inhibits TfR1 upregulation and prevents iron accumulation and lipid peroxidation-driven T cell dysfunction.\",\n      \"method\": \"Single-cell RNA sequencing, flow cytometry, CD36 depletion, p38/CEBPB inhibitor studies, intracellular iron and lipid peroxide measurements\",\n      \"journal\": \"Clinical and molecular hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq, genetic depletion, signaling pathway dissection; single lab\",\n      \"pmids\": [\"40037690\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Histone acetyltransferase Kat2a promotes ferroptosis by enhancing H3K27ac and H3K9ac enrichment on the Tfrc (and Hmox1) promoter regions, thereby increasing Tfrc transcription. ALKBH5 demethylase reduces m6A methylation on Kat2a mRNA, and YTHDF2 mediates Kat2a mRNA degradation, providing an upstream regulatory mechanism.\",\n      \"method\": \"Kat2a inhibition in vitro and in vivo, ChIP for H3K27ac/H3K9ac on Tfrc promoter, YTHDF2/ALKBH5 functional studies, ferroptosis assays in DCM model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for histone marks on specific promoter, functional inhibition, in vivo model; single lab\",\n      \"pmids\": [\"38858351\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATF3 (activating transcription factor 3) promotes osteocyte ferroptosis during aging by upregulating TfR1 expression (enhancing iron uptake) while simultaneously inhibiting SLC7A11-mediated cystine import, leading to iron overload and lipid peroxidation.\",\n      \"method\": \"Single-cell transcriptome analysis, ATF3 inhibition in aged mice, ferroptosis markers in cortical bone, TfR1 and SLC7A11 expression analysis\",\n      \"journal\": \"Cell proliferation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — scRNA-seq identification, in vivo ATF3 inhibition with functional readouts; single lab\",\n      \"pmids\": [\"38764128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HIF-2α upregulates TFR1 expression in cartilage endplate chondrocytes in response to oxidative stress and pro-inflammatory cytokines; excess TFR1-mediated iron accumulation induces ferroptosis and triggers c-GAS/STING-mediated innate immune inflammation via mitochondrial damage and mtDNA release.\",\n      \"method\": \"IDD mouse model, TfR1 siRNA knockdown, HIF-2α pathway analysis, c-GAS/STING inhibition with siRNA and ethidium bromide, western blot/immunofluorescence\",\n      \"journal\": \"Journal of orthopaedic translation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model, pathway dissection via siRNA, functional cGAS/STING rescue; single lab\",\n      \"pmids\": [\"38808263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TIMP1 regulates HGHF-induced ferroptosis in osteoblasts by inhibiting TFRC ubiquitination (preventing its proteasomal degradation), thereby increasing TFRC protein levels and promoting iron accumulation. TFRC overexpression reversed the ferroptosis inhibition caused by TIMP1 knockout.\",\n      \"method\": \"TIMP1 knockout and TFRC overexpression in osteoblasts, ubiquitination assays, ferroptosis markers, type 2 diabetic mouse model, western blot/flow cytometry\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination biochemistry, genetic rescue experiment, in vivo diabetic model; single lab\",\n      \"pmids\": [\"39578773\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RAB17 attenuates ferroptosis in endometrial cancer cells by inhibiting TFRC protein expression in a ubiquitin proteasome-dependent manner, thereby reducing iron uptake. Under low-glucose conditions, RAB17 expression increases and limits ferroptosis through the RAB17-TFRC axis.\",\n      \"method\": \"RAB17 knockdown/overexpression, TFRC protein stability/ubiquitination assays, ferroptosis phenotyping, xenograft and clinical correlation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue, ubiquitination biochemistry, in vivo xenograft; single lab\",\n      \"pmids\": [\"39242574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"NUF2 inhibits p62-mediated autophagic degradation of TFR1 via p38/MAPK signaling, thereby stabilizing TFR1 protein and promoting cholangiocarcinoma progression.\",\n      \"method\": \"NUF2 overexpression/knockdown, p62-TFR1 binding assay, p38/MAPK inhibition, autophagic flux measurement, TFR1 protein stability assays\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding and degradation assays, signaling pathway inhibition, functional cancer progression readouts; single lab\",\n      \"pmids\": [\"37056930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANXA10 knockdown induces ferroptosis by inhibiting autophagy-mediated TFRC degradation, leading to increased TFRC protein levels, labile iron accumulation, and lipid peroxidation in colorectal cancer cells.\",\n      \"method\": \"ANXA10 knockdown, TFRC protein stability measurement, autophagy flux assay (SQSTM1 accumulation), ferroptosis markers (Fe2+, MDA, ROS), immunofluorescence\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KD, autophagy flux and TFRC stability assays, multiple ferroptosis readouts; single lab\",\n      \"pmids\": [\"37666806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TfR1 is identified as the cell-surface target of the aptamer XQ-2d on pancreatic cancer cells. XQ-2d shares the same binding site on CD71 as transferrin (Tf), competitively inhibiting Tf binding, while the anti-CD71 antibody binds at a distinct site approximately 15 nm away as measured by surface energy transfer nanoruler.\",\n      \"method\": \"CD71 knockdown abolishing aptamer binding, competitive binding analysis with Tf and anti-CD71 antibody, surface energy transfer (SET) nanoruler distance measurement, molecular dynamics simulation\",\n      \"journal\": \"Journal of the American Chemical Society\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding site identified by competition assay and distance measurement, genetic knockdown confirmation; single lab\",\n      \"pmids\": [\"31185171\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"TFRC is an immediate target gene of the canonical Wnt pathway, with Myc and Tfrc expression induced within less than 1 hour of Wnt-3a stimulation in C57MG cells, earlier than other Wnt targets such as Ccnd1.\",\n      \"method\": \"Time-course gene expression analysis after Wnt-3a stimulation, classification of target gene expression chronology\",\n      \"journal\": \"Cell biology international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single expression time-course, no mechanistic dissection of how Wnt directly controls TFRC transcription\",\n      \"pmids\": [\"19353769\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"miR-320 targets the transferrin receptor 1 (TfR1/CD71) 3'UTR and suppresses TfR1 surface expression and cell proliferation in HL-60 leukemia cells during monocytic differentiation.\",\n      \"method\": \"miR-320 enforced expression in HL-60 cells, TfR1 surface expression measurement, cell proliferation assay\",\n      \"journal\": \"Experimental hematology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single cell line, single method for target validation (expression), no direct luciferase 3'UTR reporter shown in abstract\",\n      \"pmids\": [\"19135902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TFRC is essential for meiotic progression in mouse spermatocytes; TFRC knockdown via morpholino causes spermatocyte apoptosis, accumulation of leptotene/zygotene spermatocytes, arrest before pachytene, sustained γH2AX association, and SYCP1/SYCP3 dissociation beyond the sex body, indicating roles in DNA double-strand break repair and chromosomal synapsis.\",\n      \"method\": \"TFRC knockdown via morpholino oligonucleotides in neonatal testis culture, chromosomal spread technique, γH2AX/SYCP1/SYCP3 immunostaining, apoptosis assay\",\n      \"journal\": \"Zygote\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino KD with defined meiotic phenotype, chromosomal spread with molecular markers; single lab\",\n      \"pmids\": [\"33323153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10-mediated ac4C acetylation of TFRC mRNA stabilizes it, increasing TFRC expression and promoting ferroptosis in lung microvascular endothelial cells during sepsis-induced pulmonary injury.\",\n      \"method\": \"NAT10 inhibition in vitro and in vivo (sepsis rat model), ac4C assay on TFRC mRNA, ferroptosis markers, cell viability assays\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ac4C modification assay on specific mRNA target, in vivo model, functional rescue; single lab\",\n      \"pmids\": [\"39251905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TFEB promotes TFRC in cardiomyocytes via STAT3, which in turn upregulates Ccl2 expression to recruit and activate macrophages. HIF-1α regulates TFRC expression in cardiomyocytes during heart failure.\",\n      \"method\": \"TAC mouse model, ISO/PHE-stimulated cardiomyocytes, immunofluorescence for TFRC and macrophage infiltration, flow cytometry, STAT3 pathway analysis, HIF-1α manipulation\",\n      \"journal\": \"Immunity, inflammation and disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional cell signaling data present but mechanistic link between TFRC and STAT3-Ccl2 is inferential with limited biochemistry shown in abstract\",\n      \"pmids\": [\"37647427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"lncRNA-IUR-5 suppresses Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71 (TfR1), as demonstrated by RNA pulldown and RNA immunoprecipitation showing lncRNA-IUR-5 interaction with STAT5 pathway components.\",\n      \"method\": \"RNA pulldown, RNA immunoprecipitation (RIP), transcriptome RNA-seq, lncRNA-IUR KD transgenic mice, Bcr-Abl transformation assay\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — RIP shows interaction but mechanistic link between lncRNA-IUR-5 and STAT5-CD71 is not fully biochemically resolved in abstract\",\n      \"pmids\": [\"30961617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTO demethylase activity reduces m6A modification on TfRc mRNA; YTHDF1 binds m6A-modified TfRc mRNA and promotes its translation, while YTHDF2 mediates stability of SLC7A11 mRNA via m6A. Inhibition of AR transcriptional regulation of FTO by BPF exposure dysregulates this axis.\",\n      \"method\": \"ChIP for AR binding to FTO promoter, MeRIP for m6A on TfRc mRNA, RIP for YTHDF1-TfRc mRNA and YTHDF2-SLC7A11 mRNA binding, FTO overexpression\",\n      \"journal\": \"Environmental pollution\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP and RIP biochemistry establishing m6A modification and reader binding to TFRC mRNA; single lab\",\n      \"pmids\": [\"38996995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Serum iron, transferrin saturation, and hepatic Tfrc expression exhibit circadian rhythms that are maintained in constant darkness and ablated by Bmal1 knockout, demonstrating endogenous circadian control. Hepatic Tfrc expression and erythropoietic activity oscillate in opposing phases.\",\n      \"method\": \"Constant darkness housing, Bmal1 knockout mice, time-series serum iron and TSAT measurement, hepatic Tfrc qPCR, erythropoietic activity assays\",\n      \"journal\": \"American journal of hematology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic disruption of circadian machinery (Bmal1 KO) abolishes Tfrc oscillation, constant darkness control; single lab\",\n      \"pmids\": [\"39152780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"H3K9me3 (mediated by Suv39h1 methyltransferase) is enriched at the promoter and gene body of Tfr1 and represses its transcription during hemin-induced ferroptosis in neuronal cells. Inhibition of Suv39h1/H3K9me3 aggravates ferroptosis by upregulating Tfr1 expression, demonstrating a protective epigenetic mechanism.\",\n      \"method\": \"ChIP for H3K9me3 at Tfr1 promoter, Suv39h1 siRNA/inhibitor, hemin/RSL3 ferroptosis model, Tfr1 expression analysis, in vivo ICH mouse model with intracerebroventricular Suv39h1 siRNA\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP at specific promoter, genetic and pharmacological inhibition in vitro and in vivo; single lab\",\n      \"pmids\": [\"36960698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TfR1 in CD71+ regulatory T cells (Tregs) is required for Treg perinatal expansion. Treg-restricted CD71 deficiency leads to a scurfy-like autoimmune disease, impaired perinatal Treg proliferation, loss of tissue-Treg gene signature, and hepatic iron overload with increased hepcidin. CD71-null Tregs show decreased proliferation.\",\n      \"method\": \"Treg-specific conditional CD71 knockout mice, Treg proliferation assays, tissue-Treg gene signature analysis, iron metabolism measurements, hepcidin quantification, fecal microbiota analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell type-specific conditional KO with multiple defined phenotypes (autoimmunity, proliferation, iron homeostasis); rigorous in vivo model\",\n      \"pmids\": [\"38954474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TfR1 knockdown in neural cells differentiated from Alzheimer's disease patient-derived iPSCs reduces iron overload and mitochondrial dysfunction. TfR1 interacts with GSK3B and promotes GSK3B expression; GSK3B overexpression reverses the protective effects of TfR1 knockdown.\",\n      \"method\": \"TfR1 knockdown/overexpression in AD-iPS differentiated neural cells, co-immunoprecipitation for TfR1-GSK3B interaction, iron/ROS/mitochondrial membrane potential assays, GSK3B rescue experiment\",\n      \"journal\": \"European journal of medical research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for TfR1-GSK3B, genetic rescue experiments, multiple functional readouts; single lab\",\n      \"pmids\": [\"38321571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Complement C4 directly interacts with TFRC during CVB3 infection (identified by Co-IP and mass spectrometry), and this interaction leads to increased C4b production and decreased downstream complement C3. Regulating the complement C4/C3 pathway via TFRC modulates ferroptosis in CVB3-infected cardiomyocytes.\",\n      \"method\": \"Co-IP and protein mass spectrometry for TFRC-interacting proteins, Fer-1 treatment, complement C3/C4b quantification, functional ferroptosis assays\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mass spectrometry identification of C4 as TFRC binding partner, functional downstream assays; single lab\",\n      \"pmids\": [\"38169212\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TFRC (TfR1/CD71) is a type II transmembrane homodimeric glycoprotein that mediates cellular iron uptake by binding transferrin-bound iron and undergoing clathrin-mediated endocytosis via a tyrosine-based internalization motif (Tyr20); its activity, stability, and trafficking are regulated by multiple post-translational modifications including stearoylation (inhibiting JNK activation and promoting mitochondrial fusion via HUWE1/mitofusin), O-GlcNAcylation (at Ser687, controlling MARCH8-mediated ubiquitination at Lys665), palmitoylation by DHHC5 (at Cys98, controlling endocytosis rate in oligodendrocytes), and ubiquitin-mediated proteasomal degradation via NEDD4L, βTrCP, or MARCH8; its mRNA is regulated post-transcriptionally by m6A methylation (written by METTL3, read by IGF2BP2 for stabilization or YTHDF1 for translation, demethylated by FTO) and ac4C modification (by NAT10), and transcriptionally by HIF-1, HIF-2α, Sp1, ATF3, STAT5, Ahr, and the Wnt pathway; TfR1 also physically interacts with HFE in hepatocytes to regulate hepcidin production and systemic iron homeostasis, with STEAP3 to provide an accessory endocytosis signal in erythroblasts, with the IKK complex to support NF-κB signaling, with GSK3B to modulate neuronal iron metabolism, with complement C4 during viral infection, and with Musclin to transduce a thermogenic signaling pathway via cAMP/PKA; loss of TfR1 function in lymphocytes (due to internalization-defective mutations) causes combined immunodeficiency by impairing iron-dependent lymphocyte activation, while in erythroid precursors TfR1 overexpression drives ineffective erythropoiesis in β-thalassemia, and in various cell types excess TfR1-mediated iron uptake promotes ferroptosis through labile iron pool expansion and lipid peroxidation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TFRC (TfR1/CD71) is the principal cell-surface receptor for transferrin-bound iron uptake, and the depth of its post-translational, transcriptional, and trafficking regulation positions it as a central control node for cellular labile iron and, consequently, for ferroptosis [#0, #14]. Receptor internalization depends on an intact tyrosine-based motif: a homozygous p.Tyr20His substitution disrupts endocytosis, raises surface TfR1, impairs transferrin uptake, and causes a combined immunodeficiency that is rescued by iron citrate and by wild-type but not mutant TfR1, establishing iron-dependent lymphocyte activation as a nonredundant TfR1 function [#0]. Beyond constitutive iron import, TfR1 abundance and activity are tuned by multiple modifications—stearoylation that restrains JNK signaling and promotes mitochondrial fusion via HUWE1/mitofusin [#1], O-GlcNAcylation at Ser687 that licenses MARCH8 binding and Lys665 polyubiquitination [#12], and DHHC5-mediated palmitoylation at Cys98 that sets endocytosis rate in oligodendrocytes [#19]. Protein levels are further set by ubiquitin-dependent degradation through NEDD4L and βTrCP and by autophagic turnover, with multiple E3 ligases and adaptors converging on TfR1 to lower the labile iron pool and suppress ferroptosis [#5, #10, #11, #12]. TFRC mRNA is regulated by m6A methylation (METTL3 writing, IGF2BP2 stabilizing, YTHDF1 enhancing translation, FTO demethylating) and by NAT10-dependent ac4C acetylation, while its transcription is driven by HIF-1/HIF-2α, Sp1, ATF3, and Ahr and is restrained by repressive H3K9me3 chromatin [#8, #9, #7, #32, #15, #23, #6, #17, #37]. Through these inputs, excess TfR1-mediated iron import drives ferroptosis across diverse tissues, whereas physiological TfR1 also supports systemic iron homeostasis via an HFE-dependent hepatocyte function controlling hepcidin, contributes to ineffective erythropoiesis in β-thalassemia, and supports regulatory T cell and ILC3 expansion and metabolic programming [#4, #3, #38, #17]. TfR1 additionally engages non-canonical partners—the IKK complex to sustain NF-κB signaling and the myokine Musclin to gate cAMP/PKA-dependent adipocyte thermogenesis [#2, #16].\",\n  \"teleology\": [\n    {\n      \"year\": 2009,\n      \"claim\": \"Early work placed TFRC expression downstream of growth and developmental signaling, framing it as an inducible rather than purely housekeeping gene.\",\n      \"evidence\": \"Wnt-3a stimulation time-course in C57MG cells; miR-320 enforced expression in HL-60 cells\",\n      \"pmids\": [\"19353769\", \"19135902\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Wnt linkage is correlative time-course with no direct promoter mechanism\", \"miR-320 target validation lacks a direct 3'UTR reporter\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established that TfR1 has a signaling role beyond iron import by physically scaffolding the IKK complex to sustain NF-κB-dependent transcription and protect against TNFα-induced apoptosis.\",\n      \"evidence\": \"Unbiased proteomics, reciprocal Co-IP, siRNA knockdown, NF-κB reporter and chromatin binding assays\",\n      \"pmids\": [\"23016877\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of TfR1-IKK contact unresolved\", \"Whether iron import is required for the NF-κB effect not separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the genetic and structural requirement for TfR1 endocytosis in human disease, showing that a Tyr20 motif mutation causes combined immunodeficiency through defective receptor internalization rescuable by iron.\",\n      \"evidence\": \"Patient fibroblast rescue, Tfrc(Y20H/Y20H) knock-in mice, endocytosis assays, STEAP3 Co-IP\",\n      \"pmids\": [\"26642240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"STEAP3 accessory endocytosis signal only partially defined\", \"Tissue specificity of the immune phenotype not fully explained\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a lipid-modification arm of TfR1 regulation in which stearoylation suppresses TfR1-driven JNK signaling and promotes mitochondrial fusion, linking dietary fatty acids to mitochondrial dynamics.\",\n      \"evidence\": \"In vivo dietary C18:0 manipulation, Drosophila genetics, stearoylation biochemistry, mitofusin ubiquitination assay\",\n      \"pmids\": [\"26214738\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stearoylation site on TfR1 not mapped here\", \"Connection between stearoylation and canonical iron uptake unaddressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that TfR1 dosage in erythroid precursors drives ineffective erythropoiesis, with haploinsufficiency correcting iron overload in β-thalassemia.\",\n      \"evidence\": \"TfR1+/- × β-thalassemia mouse crosses, erythroid culture with apotransferrin, flow cytometry, in vivo iron measures\",\n      \"pmids\": [\"28151426\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of apotransferrin suppression of TfR1 not molecularly defined\", \"Human translatability not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed that hepatocyte TfR1's role in systemic iron homeostasis and hepcidin regulation is strictly HFE-dependent, resolving the in vivo partnership controlling iron sensing.\",\n      \"evidence\": \"Hepatocyte-specific Tfrc knockout, Tfrc/Hfe double knockout epistasis, β-thalassemia model, iron and hepcidin quantification\",\n      \"pmids\": [\"36322932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular details of TfR1-HFE-mediated hepcidin signaling not dissected here\", \"Other hepatic iron sensors not excluded\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended TfR1 function into immune and metabolic programming, establishing transcriptional repression by Ahr controls ILC3 iron metabolism and a Musclin-TfR1 axis that gates adipocyte thermogenesis.\",\n      \"evidence\": \"Tfrc conditional ablation in ILC3, Ahr ChIP and genetic ablation, metabolic assays; Musclin binding and muscle-specific KO mice with cAMP/PKA readouts\",\n      \"pmids\": [\"37709985\", \"37468484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Musclin and transferrin compete for TfR1 not defined\", \"How iron flux couples to OXPHOS-glycolysis switch mechanistically open\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a Treg-intrinsic requirement for TfR1, showing iron uptake supports perinatal Treg expansion and prevents scurfy-like autoimmunity.\",\n      \"evidence\": \"Treg-specific conditional CD71 knockout, proliferation and tissue-Treg signature analysis, iron and hepcidin measurements\",\n      \"pmids\": [\"38954474\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Iron-dependent metabolic targets in Tregs not identified\", \"Link between Treg iron and systemic hepcidin not fully mechanistic\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mapped a multilayered code controlling TfR1 protein stability through site-specific O-GlcNAcylation and competing E3 ligase pathways that set the labile iron pool and ferroptosis sensitivity.\",\n      \"evidence\": \"Ser687/Lys665 mutagenesis, MARCH8 Co-IP and ubiquitination assays; NEDD4L, βTrCP, ESR1, TIMP1, RAB17 ubiquitination/stability studies across cancer and injury models\",\n      \"pmids\": [\"38744192\", \"38302612\", \"34315867\", \"35613689\", \"39578773\", \"39242574\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy among competing E3 ligases in a single cell type unresolved\", \"Crosstalk between O-GlcNAc, palmitoylation, and ubiquitination not integrated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established RNA-level control of TFRC by m6A and ac4C, identifying writers, readers, and erasers that tune TFRC stability and translation to drive or restrain ferroptosis in vivo.\",\n      \"evidence\": \"METTL3 conditional KO, IGF2BP2/YTHDF1 RIP, FTO target identification, NAT10 ac4C assays across cardiac, hepatic, and pulmonary injury models\",\n      \"pmids\": [\"38631119\", \"33204330\", \"38834654\", \"39251905\", \"38996995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of stabilization versus translational control unclear\", \"Whether multiple RNA modifications act on the same transcripts simultaneously untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Detailed transcriptional and chromatin control converging on the Tfrc promoter, with HIF-1/HIF-2α, Sp1, ATF3, and Kat2a-driven acetylation activating, and Suv39h1/H3K9me3 repressing, transcription to set ferroptosis thresholds.\",\n      \"evidence\": \"ChIP for transcription factors and histone marks, HDAC9/HIF/Sp1 dissection, Kat2a and Suv39h1 manipulation in ischemia and cardiomyopathy models\",\n      \"pmids\": [\"37324938\", \"38858351\", \"38764128\", \"38808263\", \"35821227\", \"36960698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Combinatorial logic of these factors at the promoter not resolved\", \"Cell-type specificity of repressive versus activating control unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered trafficking and non-iron interactions of TfR1, including palmitoylation-controlled endocytosis, CCT3/ACTN4-dependent recycling, autophagic and EV-mediated turnover, and partnerships with GSK3B and complement C4.\",\n      \"evidence\": \"DHHC5 palmitoylation site mapping in oligodendrocytes, CCT3-ACTN4-TFRC Co-IP, LDELS/ESCRT/RAB27A EV secretion dissection, GSK3B and C4 Co-IP\",\n      \"pmids\": [\"39929269\", \"39210442\", \"36286616\", \"38321571\", \"38169212\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional significance of TfR1 EV secretion unknown\", \"TfR1-GSK3B and TfR1-C4 interactions rest on single-lab Co-IP\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the numerous parallel regulatory layers — PTMs, competing E3 ligases, RNA modifications, transcription factors, and trafficking machinery — are integrated within a single cell to set TfR1 surface density and iron flux remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified model reconciling competing degradation and stabilization pathways\", \"Quantitative contribution of each layer to net iron uptake unmeasured\", \"Structural basis for most non-transferrin partner interactions undetermined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 28]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [2, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6, 28]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [0, 4, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [5, 8, 12, 23]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [2, 17, 38]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 16, 36]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HFE\", \"STEAP3\", \"IKK\", \"MARCH8\", \"NEDD4L\", \"GSK3B\", \"Musclin\", \"C4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}