{"gene":"FTL","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2016,"finding":"FTL protein localizes to the nucleus of GBM cells and associates with mitotic spindles. FTL physically interacts with GADD45A (confirmed by co-immunoprecipitation), and FTL knockdown activates the GADD45A/JNK pathway, inhibiting GBM cell growth. Co-transfection of FTL impedes GADD45A-induced reduction of cell viability.","method":"Immunofluorescence, co-immunoprecipitation, siRNA knockdown, immunoblotting, cell viability assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP and multiple orthogonal methods in a single lab study","pmids":["26871431"],"is_preprint":false},{"year":2014,"finding":"The 498-499InsTC mutation in FTL substitutes the last 9 amino acids and extends the C-terminus by 16 amino acids. Cyclic voltammetry on the purified mutant protein showed this structural change severely reduces the ability of FTL to store iron. In transgenic FVB mice expressing this mutant, accumulation of mutated ferritin in brain correlated with increased iron deposition and oxidative damage with age, and progressive motor coordination deficits.","method":"Cyclic voltammetry on purified protein, transgenic mouse model (FVB and C57BL/6 backgrounds), MRI, rotarod behavioral testing, ultrastructural analysis","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct in vitro biochemical assay on purified protein combined with in vivo transgenic model with multiple orthogonal readouts","pmids":["25447222"],"is_preprint":false},{"year":2022,"finding":"NSUN5 binds FTL mRNA (shown by RNA immunoprecipitation) and methylates it at the 5-methylcytosine position; NSUN5 depletion reduces 5-methylcytosine levels on FTL RNA, lowers FTL protein, increases intracellular free iron, and leads to downregulation of GPX4 and accumulation of ROS and lipid peroxidation, promoting ferroptosis. Recognition of FTL by NSUN5 depends on recruitment of TRAP1 (shown by co-immunoprecipitation).","method":"RNA immunoprecipitation, co-immunoprecipitation, siRNA knockdown, overexpression, ROS/lipid peroxidation assays","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA IP and Co-IP with multiple functional readouts, single lab","pmids":["35249107"],"is_preprint":false},{"year":2020,"finding":"HIF-1α directly binds to the HRE-3 element in the FTL promoter to transcriptionally upregulate FTL expression under hypoxia (confirmed by luciferase reporter and ChIP assays). FTL knockdown represses EMT and reduces migration/invasion of glioma cells via the AKT/GSK3β/β-catenin signaling pathway.","method":"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, wound healing/transwell assays, western blot, subcutaneous xenograft model","journal":"Journal of experimental & clinical cancer research : CR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter for direct transcriptional regulation, functional knockdown with multiple orthogonal assays, single lab","pmids":["32677981"],"is_preprint":false},{"year":2007,"finding":"A 25 bp deletion in the FTL promoter abolishing the transcription start site causes HHCS; in lymphoblastoid cells, the deletion allele is transcribed from an alternate start site within the lower stem of the iron-responsive element (IRE), and mutation carriers have high cellular L-ferritin levels, demonstrating that disruption of the transcription start site leads to de-repression of FTL translation.","method":"Sequencing of promoter/IRE region, lymphoblastoid cell transfection/expression analysis, genetic linkage in kindred","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based validation of a promoter deletion with direct measurement of FTL protein levels, single lab","pmids":["17579362"],"is_preprint":false},{"year":2006,"finding":"A missense mutation in FTL (474G>A; A96T) causes neuroferritinopathy with early-onset bilateral pallidal involvement. Affected individuals and carrier showed abnormally low levels of serum ferritin, consistent with loss of FTL iron-storage function.","method":"Genetic sequencing, clinical biochemistry (serum ferritin), MRI","journal":"Neurology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genetic/clinical observation in a small family, no direct in vitro biochemical characterization of mutant protein","pmids":["16116125"],"is_preprint":false},{"year":2006,"finding":"Mutations in the IRE of FTL (c.-168G>A) cause hereditary hyperferritinemia cataract syndrome (HHCS) by disrupting the iron-responsive element in the 5'-UTR of FTL, leading to unregulated (constitutively high) FTL translation and elevated serum ferritin without iron overload.","method":"Genome-wide linkage analysis, sequencing of IRE region, hematological tests","journal":"Molecular vision","confidence":"Medium","confidence_rationale":"Tier 2 / Strong — IRE mechanism of FTL regulation is well established; this paper confirms the molecular basis in a family with a specific IRE mutation","pmids":["16518306"],"is_preprint":false},{"year":2025,"finding":"SIRT1 deacetylates FTL at the K181 residue (confirmed by co-immunoprecipitation and GST pulldown), upregulating FTL expression. FTL knockdown inhibits the ferroptosis-suppressive effect of SIRT1 overexpression in chondrocytes. In vivo, SIRT1 overexpression reduced OA severity via this FTL deacetylation mechanism.","method":"Co-immunoprecipitation, GST pulldown, quantitative RT-PCR, western blotting, IL-1β and DMM mouse OA models, ferroptosis assays (LDH, Fe2+, GSH, MDA, lipid ROS)","journal":"Journal of bone and mineral metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and pulldown identify K181 acetylation site, functional rescue experiments, in vitro and in vivo, single lab","pmids":["39786573"],"is_preprint":false},{"year":2026,"finding":"HERC2 (a HECT-domain E3 ubiquitin ligase) directly interacts with FTL (validated by co-immunoprecipitation and ubiquitination assay) and promotes FTL ubiquitination and degradation, leading to intracellular iron accumulation, autophagy activation, lipid peroxidation, and chondrocyte ferroptosis in osteoarthritis. HERC2 deficiency in vivo preserved cartilage integrity.","method":"Immunoprecipitation-mass spectrometry, co-immunoprecipitation, ubiquitination assay, siRNA knockdown/overexpression, molecular docking, HERC2-deficient mouse DMM model","journal":"Apoptosis : an international journal on programmed cell death","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay identify HERC2 as E3 ligase for FTL, with in vitro and in vivo validation, single lab","pmids":["41854786"],"is_preprint":false},{"year":2024,"finding":"FTL (ferritin) tightly regulates labile iron levels, and elevated FTL promotes iron-dependent DNA damage repair in ovarian cancer: iron downregulates POLQ (a HR inhibitor) and relieves its antagonism of RAD51, thereby promoting DNA repair and platinum resistance. FTH1/FTL are indispensable for this iron-triggered DNA repair pathway.","method":"Iron supplementation/chelation experiments, western blot, cell survival/migration assays, in vitro and in vivo xenograft","journal":"Cell death & disease","confidence":"Low","confidence_rationale":"Tier 3 / Weak — indirect mechanistic linkage for FTL specifically; direct biochemical interaction of FTL with POLQ/RAD51 not demonstrated","pmids":["38740757"],"is_preprint":false},{"year":2025,"finding":"Increasing neuronal FTL1 in the hippocampus of young mice alters labile iron oxidation states and promotes synaptic and cognitive features of hippocampal aging. Targeting (reducing) neuronal FTL1 in aged mouse hippocampi improves synaptic molecular changes and cognitive impairments. FTL1 knockdown-induced pro-aging effects are partially rescued by NADH supplementation, linking FTL1-mediated iron dysregulation to impaired ATP synthesis.","method":"Transcriptomics, mass spectrometry, AAV-mediated neuronal FTL1 overexpression/knockdown in mice, cognitive behavioral testing, neuronal nuclei RNA sequencing, NADH supplementation rescue","journal":"Nature aging","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo approaches (OE and KD), replicated across age groups, functional rescue experiment, published in peer-reviewed journal","pmids":["40830655"],"is_preprint":false},{"year":2025,"finding":"SCARA5 protein physically interacts with FTL (confirmed by co-immunoprecipitation) and reduces FTL ubiquitination, thereby stabilizing FTL protein. SCARA5 upregulation promotes ferroptosis in colon cancer cells through FTL; siRNA knockdown of FTL attenuates the pro-ferroptotic effect of SCARA5.","method":"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, cell ferroptosis assays","journal":"American journal of cancer research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP and single knockdown experiment, single lab","pmids":["40084377"],"is_preprint":false},{"year":2025,"finding":"YY1 transcription factor binds the FTL promoter to repress its expression; YY1 knockdown alleviates FTL induction, ferroptosis, and pulmonary fibrosis caused by polystyrene nanoplastics. PS-NPs suppress GPX4 while inducing FTL, driving lipid peroxidation.","method":"Transcriptomic and proteomic profiling, in vitro BEAS-2B cell model, in vivo mouse aspiration model, YY1 promoter binding (implied ChIP), siRNA knockdown","journal":"Materials today. Bio","confidence":"Low","confidence_rationale":"Tier 3 / Weak — promoter binding inferred but direct ChIP not explicitly stated in abstract; single lab, single publication","pmids":["41560817"],"is_preprint":false},{"year":2026,"finding":"Knockdown of FTL1 in cardiomyocytes induces ferroptosis and cellular senescence, phenotypes reversed by the ferroptosis inhibitor Ferrostatin-1, establishing FTL1 as a protective factor against cardiac ferroptosis and aging.","method":"Region-resolved quantitative proteomics, siRNA knockdown, Ferrostatin-1 rescue, aging mouse model (3, 12, 20 months)","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct loss-of-function with pharmacological rescue, multi-region proteomic context, single lab","pmids":["42177202"],"is_preprint":false},{"year":2024,"finding":"GATA3 functions as an upstream transcription factor that directly regulates FTL expression: GATA3 knockdown reduces FTL levels while GATA3 overexpression increases them. Palmitic acid suppresses FTL by inhibiting GATA3 nuclear translocation, and AMPK activation rescues FTL expression and restores trophoblast function (confirmed by chromatin immunoprecipitation and dual-luciferase reporter assay).","method":"ChIP assay, dual-luciferase reporter assay, siRNA knockdown, overexpression, palmitic acid treatment, AMPK activator treatment, high-fat diet mouse model","journal":"Hypertension (Dallas, Tex. : 1979)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter establish direct transcriptional regulation, functional in vitro and in vivo validation, single lab","pmids":["40421527"],"is_preprint":false},{"year":2024,"finding":"SPI1 (Salmonella pathogenicity island 1 transcription factor) directly upregulates FTL expression to promote glycolysis and metastasis in ovarian cancer, validated by dual-luciferase assay and ChIP.","method":"Dual-luciferase assay, chromatin immunoprecipitation, qRT-PCR, western blot, transwell assay, glycolysis measurement (ECAR, OCR), xenograft mouse model","journal":"Expert review of anticancer therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter for direct transcriptional activation, in vitro and in vivo functional rescue, single lab","pmids":["39675923"],"is_preprint":false},{"year":2022,"finding":"FTL knockdown in mesothelioma cells induces G1 cell cycle arrest accompanied by increased p21 and p27 and decreased CDK2 and phosphorylated Rb, demonstrating that FTL promotes cell cycle progression through G1 by modulating cyclin-CDK-Rb axis.","method":"siRNA knockdown, flow cytometry cell cycle analysis, western blot for p21, p27, CDK2, pRb","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single method (siRNA + western blot), single lab, no direct interaction demonstrated","pmids":["35497939"],"is_preprint":false},{"year":1997,"finding":"The FTL gene was precisely mapped to human chromosome band 19q13.3 by fluorescence in situ hybridization (FISH).","method":"In situ fluorescence hybridization (FISH)","journal":"Annales de genetique","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cytogenetic localization by FISH, standard method for chromosomal mapping","pmids":["9526618"],"is_preprint":false}],"current_model":"FTL (ferritin light chain) is a subunit of the ferritin iron-storage complex that sequesters intracellular labile iron; its translation is regulated by iron-responsive element (IRE)-binding proteins that interact with the IRE in the 5'-UTR of FTL mRNA, such that IRE mutations cause constitutive FTL over-translation (hereditary hyperferritinemia cataract syndrome), while pathogenic C-terminal frameshift mutations reduce iron-storage capacity and cause progressive neurodegeneration (neuroferritinopathy). FTL expression is transcriptionally activated by HIF-1α (via HRE-3 in the promoter under hypoxia), SPI1, and GATA3, and is repressed by YY1. Post-translationally, SIRT1 deacetylates FTL at K181 to stabilize it and suppress ferroptosis, whereas HERC2 (an E3 ubiquitin ligase) ubiquitinates and degrades FTL to promote iron accumulation and ferroptosis. NSUN5 methylates FTL mRNA (m5C) in a TRAP1-dependent manner to maintain FTL levels and resist ferroptosis. In neurons, elevated FTL1 alters labile iron oxidation states, impairing mitochondrial ATP synthesis and synaptic function to drive cognitive aging. FTL physically interacts with GADD45A to suppress the GADD45A/JNK growth-inhibitory pathway in glioblastoma, and with SCARA5 which inhibits FTL ubiquitination."},"narrative":{"mechanistic_narrative":"FTL (ferritin light chain) is a subunit of the ferritin iron-storage complex that buffers intracellular labile iron and thereby gates iron-dependent oxidative cell death (ferroptosis), with its loss in multiple tissues triggering iron accumulation, lipid peroxidation, and ferroptotic and senescent phenotypes [PMID:42177202, PMID:35249107]. Direct biochemical and transgenic evidence establishes that the iron-storage function depends on FTL's C-terminus: a frameshift extending the C-terminus severely impairs iron storage and, in transgenic mice, drives brain iron deposition, oxidative damage, and progressive motor deficits, the basis of neuroferritinopathy [PMID:25447222]. FTL translation is normally restrained by the iron-responsive element in its 5'-UTR; disruption of this control—via IRE mutation or loss of the transcription start site—causes constitutive FTL over-translation and hereditary hyperferritinemia cataract syndrome [PMID:16518306, PMID:17579362]. Beyond translational control, FTL protein levels are set by competing post-translational inputs: the E3 ubiquitin ligase HERC2 ubiquitinates FTL to promote its degradation and drive ferroptosis [PMID:41854786], whereas SIRT1-mediated deacetylation at K181 stabilizes FTL and suppresses ferroptosis [PMID:39786573], and NSUN5-dependent m5C methylation of FTL mRNA maintains FTL protein in a TRAP1-dependent manner [PMID:35249107]. FTL transcription is positively controlled by HIF-1α (HRE-3), SPI1, and GATA3 [PMID:32677981, PMID:39675923, PMID:40421527]. In cancer, FTL supports proliferation and invasion—it localizes to the nucleus and mitotic spindle, binds GADD45A to suppress the GADD45A/JNK growth-inhibitory pathway in glioblastoma, and promotes glioma EMT via AKT/GSK3β/β-catenin signaling [PMID:26871431, PMID:32677981]. In neurons, elevated FTL1 alters labile iron oxidation states to impair ATP synthesis and synaptic function, promoting hippocampal aging [PMID:40830655].","teleology":[{"year":1997,"claim":"Establishing the genomic location of FTL provided the anchor for subsequent linkage of inherited iron-storage and cataract syndromes to the locus.","evidence":"FISH mapping to human chromosome 19q13.3","pmids":["9526618"],"confidence":"Medium","gaps":["Localization alone gives no functional or regulatory information","Does not connect the gene to any phenotype"]},{"year":2006,"claim":"Family genetics resolved how distinct FTL lesions cause opposite clinical phenotypes—IRE mutations de-repress translation to cause hyperferritinemia, while coding mutations impair iron storage to cause neurodegeneration.","evidence":"Linkage and sequencing of the IRE (HHCS) and a missense allele (neuroferritinopathy) with serum ferritin measurement","pmids":["16518306","16116125"],"confidence":"Medium","gaps":["A96T mutant protein was not biochemically characterized in vitro","Mechanism linking reduced iron storage to pallidal neurodegeneration not established"]},{"year":2007,"claim":"A promoter deletion abolishing the transcription start site showed that loss of normal start-site usage forces transcription from within the IRE stem, de-repressing FTL translation—broadening the molecular routes to HHCS beyond point IRE mutations.","evidence":"Promoter/IRE sequencing and expression analysis in lymphoblastoid cells from a kindred","pmids":["17579362"],"confidence":"Medium","gaps":["Single kindred","Quantitative contribution of the alternate start site versus IRE disruption not separated"]},{"year":2014,"claim":"Direct biochemistry on purified mutant protein plus a transgenic model causally connected a C-terminal frameshift to defective iron storage and age-dependent neurodegeneration, defining the disease mechanism of neuroferritinopathy.","evidence":"Cyclic voltammetry on purified protein and FVB transgenic mice with MRI, rotarod, and ultrastructure","pmids":["25447222"],"confidence":"High","gaps":["Whether mutant subunits act dominant-negatively within mixed ferritin shells not resolved","Cell-type specificity of brain iron deposition not dissected"]},{"year":2016,"claim":"FTL was shown to have a non-canonical pro-proliferative role independent of iron storage, physically engaging GADD45A to block the GADD45A/JNK growth-inhibitory axis in glioblastoma.","evidence":"Immunofluorescence, reciprocal co-immunoprecipitation, siRNA knockdown, and viability assays in GBM cells","pmids":["26871431"],"confidence":"Medium","gaps":["Nuclear/spindle localization mechanism for FTL not explained","Direct binding interface with GADD45A not mapped"]},{"year":2020,"claim":"FTL was placed downstream of hypoxic signaling, with HIF-1α directly activating FTL transcription and FTL driving EMT and invasion in glioma.","evidence":"Luciferase reporter and ChIP for HRE-3 binding, knockdown with migration/invasion assays and xenografts","pmids":["32677981"],"confidence":"Medium","gaps":["How FTL connects mechanistically to AKT/GSK3β/β-catenin not defined","Single lab"]},{"year":2022,"claim":"An RNA-level control mechanism was added: NSUN5-mediated m5C methylation of FTL mRNA, recruited via TRAP1, maintains FTL protein and protects against ferroptosis.","evidence":"RNA immunoprecipitation, co-IP, knockdown/overexpression with ROS and lipid peroxidation readouts","pmids":["35249107"],"confidence":"Medium","gaps":["The methylated cytosine position(s) on FTL mRNA not mapped","How m5C stabilizes or enhances translation of FTL not defined"]},{"year":2024,"claim":"Additional transcription factors (SPI1, GATA3) were established as direct FTL activators linking it to cancer metabolism and trophoblast function, and FTL was tied to iron-driven DNA repair and platinum resistance.","evidence":"ChIP and dual-luciferase for SPI1 and GATA3; iron supplementation/chelation experiments for the POLQ/RAD51 repair axis","pmids":["39675923","40421527","38740757"],"confidence":"Medium","gaps":["The DNA-repair linkage is indirect, with no direct FTL-POLQ/RAD51 interaction shown","How multiple TFs are integrated on the FTL promoter not resolved"]},{"year":2025,"claim":"Post-translational control of FTL stability was defined through opposing acetylation and ubiquitination inputs, and FTL1 was shown to causally regulate neuronal aging through iron-oxidation-state effects on ATP synthesis.","evidence":"Co-IP/GST pulldown mapping SIRT1 deacetylation at K181; SCARA5 co-IP and ubiquitination assay; AAV neuronal FTL1 overexpression/knockdown with NADH rescue in mice","pmids":["39786573","40084377","40830655"],"confidence":"Medium","gaps":["How K181 acetylation status is sensed by degradation machinery not defined","SCARA5-FTL finding rests on single Co-IP/knockdown","Molecular basis for altered iron oxidation state in neurons not established"]},{"year":2026,"claim":"HERC2 was identified as a direct E3 ubiquitin ligase for FTL, and loss-of-function across cardiomyocytes and chondrocytes confirmed FTL as a general protective factor whose depletion triggers ferroptosis and senescence.","evidence":"IP-MS, co-IP, ubiquitination assay, and HERC2-deficient mouse OA model; FTL1 knockdown with Ferrostatin-1 rescue in cardiomyocytes","pmids":["41854786","42177202"],"confidence":"Medium","gaps":["HERC2 ubiquitination site(s) on FTL not mapped","Whether HERC2 and SIRT1/SCARA5 act on the same FTL pool not tested"]},{"year":null,"claim":"How the multiple converging regulatory layers—IRE translational control, mRNA m5C methylation, transcriptional activation/repression, and competing acetylation/ubiquitination—are integrated to set FTL levels in a tissue-specific manner remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No study reconciles transcriptional, translational, and post-translational FTL control in one system","Structural consequence of K181 modification and HERC2 ubiquitination on the ferritin shell unknown","Nuclear/spindle-associated functions of FTL mechanistically uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[1,13,2]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[2,8,13]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,6,4]}],"complexes":["ferritin"],"partners":["GADD45A","HERC2","SIRT1","SCARA5","NSUN5","TRAP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P02792","full_name":"Ferritin light chain","aliases":[],"length_aa":175,"mass_kda":20.0,"function":"Stores iron in a soluble, non-toxic, readily available form. Important for iron homeostasis. Iron is taken up in the ferrous form and deposited as ferric hydroxides after oxidation. Also plays a role in delivery of iron to cells. Mediates iron uptake in capsule cells of the developing kidney (By similarity). Delivery to lysosomes by the cargo receptor NCOA4 for autophagic degradation and release or iron (PubMed:24695223)","subcellular_location":"Cytoplasmic vesicle, autophagosome; Cytoplasm; Autolysosome","url":"https://www.uniprot.org/uniprotkb/P02792/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FTL","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FTL","total_profiled":1310},"omim":[{"mim_id":"620669","title":"NEURODEGENERATION WITH BRAIN IRON ACCUMULATION 9; NBIA9","url":"https://www.omim.org/entry/620669"},{"mim_id":"620536","title":"ALPORT SYNDROME 3B, AUTOSOMAL RECESSIVE; ATS3B","url":"https://www.omim.org/entry/620536"},{"mim_id":"617288","title":"SERINE PEPTIDASE INHIBITOR, KAZAL-TYPE, 7; SPINK7","url":"https://www.omim.org/entry/617288"},{"mim_id":"615604","title":"L-FERRITIN DEFICIENCY; LFTD","url":"https://www.omim.org/entry/615604"},{"mim_id":"612754","title":"GLUTAREDOXIN 3; GLRX3","url":"https://www.omim.org/entry/612754"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":14257.7}],"url":"https://www.proteinatlas.org/search/FTL"},"hgnc":{"alias_symbol":["MGC71996","NBIA3","FTL1"],"prev_symbol":[]},"alphafold":{"accession":"P02792","domains":[{"cath_id":"1.20.1260.10","chopping":"10-171","consensus_level":"high","plddt":97.816,"start":10,"end":171}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P02792","model_url":"https://alphafold.ebi.ac.uk/files/AF-P02792-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P02792-F1-predicted_aligned_error_v6.png","plddt_mean":96.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FTL","jax_strain_url":"https://www.jax.org/strain/search?query=FTL"},"sequence":{"accession":"P02792","fasta_url":"https://rest.uniprot.org/uniprotkb/P02792.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P02792/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P02792"}},"corpus_meta":[{"pmid":"17142829","id":"PMC_17142829","title":"Clinical features and natural history of neuroferritinopathy caused by the FTL1 460InsA mutation.","date":"2006","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/17142829","citation_count":143,"is_preprint":false},{"pmid":"32677981","id":"PMC_32677981","title":"Hypoxia induced ferritin light chain (FTL) promoted epithelia mesenchymal transition and chemoresistance of glioma.","date":"2020","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/32677981","citation_count":128,"is_preprint":false},{"pmid":"35249107","id":"PMC_35249107","title":"The NSUN5-FTH1/FTL pathway mediates ferroptosis in bone marrow-derived mesenchymal stem cells.","date":"2022","source":"Cell death discovery","url":"https://pubmed.ncbi.nlm.nih.gov/35249107","citation_count":94,"is_preprint":false},{"pmid":"19377037","id":"PMC_19377037","title":"Transducin beta-like gene FTL1 is essential for pathogenesis in Fusarium graminearum.","date":"2009","source":"Eukaryotic cell","url":"https://pubmed.ncbi.nlm.nih.gov/19377037","citation_count":75,"is_preprint":false},{"pmid":"16116125","id":"PMC_16116125","title":"Neuroferritinopathy: missense mutation in FTL causing early-onset bilateral pallidal involvement.","date":"2005","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/16116125","citation_count":66,"is_preprint":false},{"pmid":"26871431","id":"PMC_26871431","title":"Expression of Ferritin Light Chain (FTL) Is Elevated in Glioblastoma, and FTL Silencing Inhibits Glioblastoma Cell Proliferation via the GADD45/JNK Pathway.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26871431","citation_count":52,"is_preprint":false},{"pmid":"31675755","id":"PMC_31675755","title":"Ferritin Light Chain (FTL) competes with long noncoding RNA Linc00467 for miR-133b binding site to regulate chemoresistance and metastasis of colorectal cancer.","date":"2020","source":"Carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/31675755","citation_count":41,"is_preprint":false},{"pmid":"25447222","id":"PMC_25447222","title":"A novel neuroferritinopathy mouse model (FTL 498InsTC) shows progressive brain iron dysregulation, morphological signs of early neurodegeneration and motor coordination deficits.","date":"2014","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/25447222","citation_count":37,"is_preprint":false},{"pmid":"20696823","id":"PMC_20696823","title":"The fslE homolog, FTL_0439 (fupA/B), mediates siderophore-dependent iron uptake in Francisella tularensis LVS.","date":"2010","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/20696823","citation_count":33,"is_preprint":false},{"pmid":"38740757","id":"PMC_38740757","title":"Iron promotes ovarian cancer malignancy and advances platinum resistance by enhancing DNA repair via FTH1/FTL/POLQ/RAD51 axis.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/38740757","citation_count":30,"is_preprint":false},{"pmid":"16518306","id":"PMC_16518306","title":"Sutural cataract associated with a mutation in the ferritin light chain gene (FTL) in a family of Indian origin.","date":"2006","source":"Molecular vision","url":"https://pubmed.ncbi.nlm.nih.gov/16518306","citation_count":29,"is_preprint":false},{"pmid":"25976471","id":"PMC_25976471","title":"Hereditary hemochromatosis type 1 phenotype modifiers in Italian patients. 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FTL physically interacts with GADD45A (confirmed by co-immunoprecipitation), and FTL knockdown activates the GADD45A/JNK pathway, inhibiting GBM cell growth. Co-transfection of FTL impedes GADD45A-induced reduction of cell viability.\",\n      \"method\": \"Immunofluorescence, co-immunoprecipitation, siRNA knockdown, immunoblotting, cell viability assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP and multiple orthogonal methods in a single lab study\",\n      \"pmids\": [\"26871431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The 498-499InsTC mutation in FTL substitutes the last 9 amino acids and extends the C-terminus by 16 amino acids. Cyclic voltammetry on the purified mutant protein showed this structural change severely reduces the ability of FTL to store iron. In transgenic FVB mice expressing this mutant, accumulation of mutated ferritin in brain correlated with increased iron deposition and oxidative damage with age, and progressive motor coordination deficits.\",\n      \"method\": \"Cyclic voltammetry on purified protein, transgenic mouse model (FVB and C57BL/6 backgrounds), MRI, rotarod behavioral testing, ultrastructural analysis\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct in vitro biochemical assay on purified protein combined with in vivo transgenic model with multiple orthogonal readouts\",\n      \"pmids\": [\"25447222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NSUN5 binds FTL mRNA (shown by RNA immunoprecipitation) and methylates it at the 5-methylcytosine position; NSUN5 depletion reduces 5-methylcytosine levels on FTL RNA, lowers FTL protein, increases intracellular free iron, and leads to downregulation of GPX4 and accumulation of ROS and lipid peroxidation, promoting ferroptosis. Recognition of FTL by NSUN5 depends on recruitment of TRAP1 (shown by co-immunoprecipitation).\",\n      \"method\": \"RNA immunoprecipitation, co-immunoprecipitation, siRNA knockdown, overexpression, ROS/lipid peroxidation assays\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA IP and Co-IP with multiple functional readouts, single lab\",\n      \"pmids\": [\"35249107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HIF-1α directly binds to the HRE-3 element in the FTL promoter to transcriptionally upregulate FTL expression under hypoxia (confirmed by luciferase reporter and ChIP assays). FTL knockdown represses EMT and reduces migration/invasion of glioma cells via the AKT/GSK3β/β-catenin signaling pathway.\",\n      \"method\": \"Luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, wound healing/transwell assays, western blot, subcutaneous xenograft model\",\n      \"journal\": \"Journal of experimental & clinical cancer research : CR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter for direct transcriptional regulation, functional knockdown with multiple orthogonal assays, single lab\",\n      \"pmids\": [\"32677981\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A 25 bp deletion in the FTL promoter abolishing the transcription start site causes HHCS; in lymphoblastoid cells, the deletion allele is transcribed from an alternate start site within the lower stem of the iron-responsive element (IRE), and mutation carriers have high cellular L-ferritin levels, demonstrating that disruption of the transcription start site leads to de-repression of FTL translation.\",\n      \"method\": \"Sequencing of promoter/IRE region, lymphoblastoid cell transfection/expression analysis, genetic linkage in kindred\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based validation of a promoter deletion with direct measurement of FTL protein levels, single lab\",\n      \"pmids\": [\"17579362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"A missense mutation in FTL (474G>A; A96T) causes neuroferritinopathy with early-onset bilateral pallidal involvement. Affected individuals and carrier showed abnormally low levels of serum ferritin, consistent with loss of FTL iron-storage function.\",\n      \"method\": \"Genetic sequencing, clinical biochemistry (serum ferritin), MRI\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genetic/clinical observation in a small family, no direct in vitro biochemical characterization of mutant protein\",\n      \"pmids\": [\"16116125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mutations in the IRE of FTL (c.-168G>A) cause hereditary hyperferritinemia cataract syndrome (HHCS) by disrupting the iron-responsive element in the 5'-UTR of FTL, leading to unregulated (constitutively high) FTL translation and elevated serum ferritin without iron overload.\",\n      \"method\": \"Genome-wide linkage analysis, sequencing of IRE region, hematological tests\",\n      \"journal\": \"Molecular vision\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Strong — IRE mechanism of FTL regulation is well established; this paper confirms the molecular basis in a family with a specific IRE mutation\",\n      \"pmids\": [\"16518306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIRT1 deacetylates FTL at the K181 residue (confirmed by co-immunoprecipitation and GST pulldown), upregulating FTL expression. FTL knockdown inhibits the ferroptosis-suppressive effect of SIRT1 overexpression in chondrocytes. In vivo, SIRT1 overexpression reduced OA severity via this FTL deacetylation mechanism.\",\n      \"method\": \"Co-immunoprecipitation, GST pulldown, quantitative RT-PCR, western blotting, IL-1β and DMM mouse OA models, ferroptosis assays (LDH, Fe2+, GSH, MDA, lipid ROS)\",\n      \"journal\": \"Journal of bone and mineral metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and pulldown identify K181 acetylation site, functional rescue experiments, in vitro and in vivo, single lab\",\n      \"pmids\": [\"39786573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"HERC2 (a HECT-domain E3 ubiquitin ligase) directly interacts with FTL (validated by co-immunoprecipitation and ubiquitination assay) and promotes FTL ubiquitination and degradation, leading to intracellular iron accumulation, autophagy activation, lipid peroxidation, and chondrocyte ferroptosis in osteoarthritis. HERC2 deficiency in vivo preserved cartilage integrity.\",\n      \"method\": \"Immunoprecipitation-mass spectrometry, co-immunoprecipitation, ubiquitination assay, siRNA knockdown/overexpression, molecular docking, HERC2-deficient mouse DMM model\",\n      \"journal\": \"Apoptosis : an international journal on programmed cell death\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay identify HERC2 as E3 ligase for FTL, with in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"41854786\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTL (ferritin) tightly regulates labile iron levels, and elevated FTL promotes iron-dependent DNA damage repair in ovarian cancer: iron downregulates POLQ (a HR inhibitor) and relieves its antagonism of RAD51, thereby promoting DNA repair and platinum resistance. FTH1/FTL are indispensable for this iron-triggered DNA repair pathway.\",\n      \"method\": \"Iron supplementation/chelation experiments, western blot, cell survival/migration assays, in vitro and in vivo xenograft\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — indirect mechanistic linkage for FTL specifically; direct biochemical interaction of FTL with POLQ/RAD51 not demonstrated\",\n      \"pmids\": [\"38740757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Increasing neuronal FTL1 in the hippocampus of young mice alters labile iron oxidation states and promotes synaptic and cognitive features of hippocampal aging. Targeting (reducing) neuronal FTL1 in aged mouse hippocampi improves synaptic molecular changes and cognitive impairments. FTL1 knockdown-induced pro-aging effects are partially rescued by NADH supplementation, linking FTL1-mediated iron dysregulation to impaired ATP synthesis.\",\n      \"method\": \"Transcriptomics, mass spectrometry, AAV-mediated neuronal FTL1 overexpression/knockdown in mice, cognitive behavioral testing, neuronal nuclei RNA sequencing, NADH supplementation rescue\",\n      \"journal\": \"Nature aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo approaches (OE and KD), replicated across age groups, functional rescue experiment, published in peer-reviewed journal\",\n      \"pmids\": [\"40830655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SCARA5 protein physically interacts with FTL (confirmed by co-immunoprecipitation) and reduces FTL ubiquitination, thereby stabilizing FTL protein. SCARA5 upregulation promotes ferroptosis in colon cancer cells through FTL; siRNA knockdown of FTL attenuates the pro-ferroptotic effect of SCARA5.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, ubiquitination assay, cell ferroptosis assays\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP and single knockdown experiment, single lab\",\n      \"pmids\": [\"40084377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"YY1 transcription factor binds the FTL promoter to repress its expression; YY1 knockdown alleviates FTL induction, ferroptosis, and pulmonary fibrosis caused by polystyrene nanoplastics. PS-NPs suppress GPX4 while inducing FTL, driving lipid peroxidation.\",\n      \"method\": \"Transcriptomic and proteomic profiling, in vitro BEAS-2B cell model, in vivo mouse aspiration model, YY1 promoter binding (implied ChIP), siRNA knockdown\",\n      \"journal\": \"Materials today. Bio\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — promoter binding inferred but direct ChIP not explicitly stated in abstract; single lab, single publication\",\n      \"pmids\": [\"41560817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Knockdown of FTL1 in cardiomyocytes induces ferroptosis and cellular senescence, phenotypes reversed by the ferroptosis inhibitor Ferrostatin-1, establishing FTL1 as a protective factor against cardiac ferroptosis and aging.\",\n      \"method\": \"Region-resolved quantitative proteomics, siRNA knockdown, Ferrostatin-1 rescue, aging mouse model (3, 12, 20 months)\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct loss-of-function with pharmacological rescue, multi-region proteomic context, single lab\",\n      \"pmids\": [\"42177202\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GATA3 functions as an upstream transcription factor that directly regulates FTL expression: GATA3 knockdown reduces FTL levels while GATA3 overexpression increases them. Palmitic acid suppresses FTL by inhibiting GATA3 nuclear translocation, and AMPK activation rescues FTL expression and restores trophoblast function (confirmed by chromatin immunoprecipitation and dual-luciferase reporter assay).\",\n      \"method\": \"ChIP assay, dual-luciferase reporter assay, siRNA knockdown, overexpression, palmitic acid treatment, AMPK activator treatment, high-fat diet mouse model\",\n      \"journal\": \"Hypertension (Dallas, Tex. : 1979)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter establish direct transcriptional regulation, functional in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"40421527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPI1 (Salmonella pathogenicity island 1 transcription factor) directly upregulates FTL expression to promote glycolysis and metastasis in ovarian cancer, validated by dual-luciferase assay and ChIP.\",\n      \"method\": \"Dual-luciferase assay, chromatin immunoprecipitation, qRT-PCR, western blot, transwell assay, glycolysis measurement (ECAR, OCR), xenograft mouse model\",\n      \"journal\": \"Expert review of anticancer therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter for direct transcriptional activation, in vitro and in vivo functional rescue, single lab\",\n      \"pmids\": [\"39675923\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FTL knockdown in mesothelioma cells induces G1 cell cycle arrest accompanied by increased p21 and p27 and decreased CDK2 and phosphorylated Rb, demonstrating that FTL promotes cell cycle progression through G1 by modulating cyclin-CDK-Rb axis.\",\n      \"method\": \"siRNA knockdown, flow cytometry cell cycle analysis, western blot for p21, p27, CDK2, pRb\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single method (siRNA + western blot), single lab, no direct interaction demonstrated\",\n      \"pmids\": [\"35497939\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The FTL gene was precisely mapped to human chromosome band 19q13.3 by fluorescence in situ hybridization (FISH).\",\n      \"method\": \"In situ fluorescence hybridization (FISH)\",\n      \"journal\": \"Annales de genetique\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cytogenetic localization by FISH, standard method for chromosomal mapping\",\n      \"pmids\": [\"9526618\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FTL (ferritin light chain) is a subunit of the ferritin iron-storage complex that sequesters intracellular labile iron; its translation is regulated by iron-responsive element (IRE)-binding proteins that interact with the IRE in the 5'-UTR of FTL mRNA, such that IRE mutations cause constitutive FTL over-translation (hereditary hyperferritinemia cataract syndrome), while pathogenic C-terminal frameshift mutations reduce iron-storage capacity and cause progressive neurodegeneration (neuroferritinopathy). FTL expression is transcriptionally activated by HIF-1α (via HRE-3 in the promoter under hypoxia), SPI1, and GATA3, and is repressed by YY1. Post-translationally, SIRT1 deacetylates FTL at K181 to stabilize it and suppress ferroptosis, whereas HERC2 (an E3 ubiquitin ligase) ubiquitinates and degrades FTL to promote iron accumulation and ferroptosis. NSUN5 methylates FTL mRNA (m5C) in a TRAP1-dependent manner to maintain FTL levels and resist ferroptosis. In neurons, elevated FTL1 alters labile iron oxidation states, impairing mitochondrial ATP synthesis and synaptic function to drive cognitive aging. FTL physically interacts with GADD45A to suppress the GADD45A/JNK growth-inhibitory pathway in glioblastoma, and with SCARA5 which inhibits FTL ubiquitination.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FTL (ferritin light chain) is a subunit of the ferritin iron-storage complex that buffers intracellular labile iron and thereby gates iron-dependent oxidative cell death (ferroptosis), with its loss in multiple tissues triggering iron accumulation, lipid peroxidation, and ferroptotic and senescent phenotypes [#13, #2]. Direct biochemical and transgenic evidence establishes that the iron-storage function depends on FTL's C-terminus: a frameshift extending the C-terminus severely impairs iron storage and, in transgenic mice, drives brain iron deposition, oxidative damage, and progressive motor deficits, the basis of neuroferritinopathy [#1]. FTL translation is normally restrained by the iron-responsive element in its 5'-UTR; disruption of this control—via IRE mutation or loss of the transcription start site—causes constitutive FTL over-translation and hereditary hyperferritinemia cataract syndrome [#6, #4]. Beyond translational control, FTL protein levels are set by competing post-translational inputs: the E3 ubiquitin ligase HERC2 ubiquitinates FTL to promote its degradation and drive ferroptosis [#8], whereas SIRT1-mediated deacetylation at K181 stabilizes FTL and suppresses ferroptosis [#7], and NSUN5-dependent m5C methylation of FTL mRNA maintains FTL protein in a TRAP1-dependent manner [#2]. FTL transcription is positively controlled by HIF-1\\u03b1 (HRE-3), SPI1, and GATA3 [#3, #15, #14]. In cancer, FTL supports proliferation and invasion—it localizes to the nucleus and mitotic spindle, binds GADD45A to suppress the GADD45A/JNK growth-inhibitory pathway in glioblastoma, and promotes glioma EMT via AKT/GSK3\\u03b2/\\u03b2-catenin signaling [#0, #3]. In neurons, elevated FTL1 alters labile iron oxidation states to impair ATP synthesis and synaptic function, promoting hippocampal aging [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing the genomic location of FTL provided the anchor for subsequent linkage of inherited iron-storage and cataract syndromes to the locus.\",\n      \"evidence\": \"FISH mapping to human chromosome 19q13.3\",\n      \"pmids\": [\"9526618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Localization alone gives no functional or regulatory information\", \"Does not connect the gene to any phenotype\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Family genetics resolved how distinct FTL lesions cause opposite clinical phenotypes—IRE mutations de-repress translation to cause hyperferritinemia, while coding mutations impair iron storage to cause neurodegeneration.\",\n      \"evidence\": \"Linkage and sequencing of the IRE (HHCS) and a missense allele (neuroferritinopathy) with serum ferritin measurement\",\n      \"pmids\": [\"16518306\", \"16116125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"A96T mutant protein was not biochemically characterized in vitro\", \"Mechanism linking reduced iron storage to pallidal neurodegeneration not established\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"A promoter deletion abolishing the transcription start site showed that loss of normal start-site usage forces transcription from within the IRE stem, de-repressing FTL translation—broadening the molecular routes to HHCS beyond point IRE mutations.\",\n      \"evidence\": \"Promoter/IRE sequencing and expression analysis in lymphoblastoid cells from a kindred\",\n      \"pmids\": [\"17579362\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single kindred\", \"Quantitative contribution of the alternate start site versus IRE disruption not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Direct biochemistry on purified mutant protein plus a transgenic model causally connected a C-terminal frameshift to defective iron storage and age-dependent neurodegeneration, defining the disease mechanism of neuroferritinopathy.\",\n      \"evidence\": \"Cyclic voltammetry on purified protein and FVB transgenic mice with MRI, rotarod, and ultrastructure\",\n      \"pmids\": [\"25447222\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mutant subunits act dominant-negatively within mixed ferritin shells not resolved\", \"Cell-type specificity of brain iron deposition not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"FTL was shown to have a non-canonical pro-proliferative role independent of iron storage, physically engaging GADD45A to block the GADD45A/JNK growth-inhibitory axis in glioblastoma.\",\n      \"evidence\": \"Immunofluorescence, reciprocal co-immunoprecipitation, siRNA knockdown, and viability assays in GBM cells\",\n      \"pmids\": [\"26871431\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear/spindle localization mechanism for FTL not explained\", \"Direct binding interface with GADD45A not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"FTL was placed downstream of hypoxic signaling, with HIF-1\\u03b1 directly activating FTL transcription and FTL driving EMT and invasion in glioma.\",\n      \"evidence\": \"Luciferase reporter and ChIP for HRE-3 binding, knockdown with migration/invasion assays and xenografts\",\n      \"pmids\": [\"32677981\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How FTL connects mechanistically to AKT/GSK3\\u03b2/\\u03b2-catenin not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"An RNA-level control mechanism was added: NSUN5-mediated m5C methylation of FTL mRNA, recruited via TRAP1, maintains FTL protein and protects against ferroptosis.\",\n      \"evidence\": \"RNA immunoprecipitation, co-IP, knockdown/overexpression with ROS and lipid peroxidation readouts\",\n      \"pmids\": [\"35249107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The methylated cytosine position(s) on FTL mRNA not mapped\", \"How m5C stabilizes or enhances translation of FTL not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Additional transcription factors (SPI1, GATA3) were established as direct FTL activators linking it to cancer metabolism and trophoblast function, and FTL was tied to iron-driven DNA repair and platinum resistance.\",\n      \"evidence\": \"ChIP and dual-luciferase for SPI1 and GATA3; iron supplementation/chelation experiments for the POLQ/RAD51 repair axis\",\n      \"pmids\": [\"39675923\", \"40421527\", \"38740757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The DNA-repair linkage is indirect, with no direct FTL-POLQ/RAD51 interaction shown\", \"How multiple TFs are integrated on the FTL promoter not resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Post-translational control of FTL stability was defined through opposing acetylation and ubiquitination inputs, and FTL1 was shown to causally regulate neuronal aging through iron-oxidation-state effects on ATP synthesis.\",\n      \"evidence\": \"Co-IP/GST pulldown mapping SIRT1 deacetylation at K181; SCARA5 co-IP and ubiquitination assay; AAV neuronal FTL1 overexpression/knockdown with NADH rescue in mice\",\n      \"pmids\": [\"39786573\", \"40084377\", \"40830655\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How K181 acetylation status is sensed by degradation machinery not defined\", \"SCARA5-FTL finding rests on single Co-IP/knockdown\", \"Molecular basis for altered iron oxidation state in neurons not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"HERC2 was identified as a direct E3 ubiquitin ligase for FTL, and loss-of-function across cardiomyocytes and chondrocytes confirmed FTL as a general protective factor whose depletion triggers ferroptosis and senescence.\",\n      \"evidence\": \"IP-MS, co-IP, ubiquitination assay, and HERC2-deficient mouse OA model; FTL1 knockdown with Ferrostatin-1 rescue in cardiomyocytes\",\n      \"pmids\": [\"41854786\", \"42177202\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HERC2 ubiquitination site(s) on FTL not mapped\", \"Whether HERC2 and SIRT1/SCARA5 act on the same FTL pool not tested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple converging regulatory layers—IRE translational control, mRNA m5C methylation, transcriptional activation/repression, and competing acetylation/ubiquitination—are integrated to set FTL levels in a tissue-specific manner remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No study reconciles transcriptional, translational, and post-translational FTL control in one system\", \"Structural consequence of K181 modification and HERC2 ubiquitination on the ferritin shell unknown\", \"Nuclear/spindle-associated functions of FTL mechanistically uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [1, 13, 2]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [2, 8, 13]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 6, 4]}\n    ],\n    \"complexes\": [\"ferritin\"],\n    \"partners\": [\"GADD45A\", \"HERC2\", \"SIRT1\", \"SCARA5\", \"NSUN5\", \"TRAP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}