{"gene":"FTH1","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":2002,"finding":"PLIF (an FTH1-related protein from placenta) is composed of the FTH1 ferritin heavy chain sequence lacking the 65 C-terminal amino acids substituted with a novel 48 amino acid domain (C48); unlike FTH1, PLIF mRNA lacks the iron response element in the 5'-UTR, indicating iron-independent synthesis; PLIF localizes to syncytiotrophoblasts at the fetal-maternal interface and inhibits peripheral blood mononuclear cell proliferation and mixed lymphocyte reactions in vitro.","method":"cDNA cloning, immunolocalization, in vitro lymphocyte proliferation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cloning and functional in vitro assays in a single study; localization confirmed by immunostaining","pmids":["11821435"],"is_preprint":false},{"year":2003,"finding":"The C48 domain of PLIF (the FTH1-derived immunomodulatory ferritin) induces IL-10 production in monocytes through a calcium/calmodulin-p38 MAP kinase signaling pathway; ERK1/2, also activated by C48, exerts a limiting effect on IL-10 production.","method":"Cytokine ELISA, pharmacological inhibitors of calmodulin and p38 MAPK","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway dissected with multiple pharmacological tools in a single lab","pmids":["12670872"],"is_preprint":false},{"year":2011,"finding":"FTH1 physically interacts with the apoptosis regulator Daxx, as demonstrated by yeast two-hybrid screening, GST pull-down, and co-immunoprecipitation; FTH1 inhibits Daxx-mediated apoptosis by suppressing activation of the Fas-Daxx-ASK1-JNK1 signaling pathway.","method":"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, JNK pathway activity assays","journal":"Molecular biology reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three orthogonal binding methods plus functional apoptosis readout in a single study","pmids":["21573799"],"is_preprint":false},{"year":2014,"finding":"MBD5 regulates Fth1 transcription in the intestine through the histone acetyltransferase KAT2A: MBD5 deletion reduces histone H4 acetylation at the Fth1 promoter, decreases intestinal Fth1 mRNA, and causes iron overload in mice; Fth1 promoter-reporter assays show MBD5 enhances Fth1 transcription in a dose-dependent manner.","method":"Conditional knockout mice, luciferase promoter assay, chromatin histone acetylation analysis, serum/liver iron measurements","journal":"British journal of haematology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vivo genetic model corroborated by promoter-reporter assay and ChIP-level histone acetylation data","pmids":["24750026"],"is_preprint":false},{"year":2016,"finding":"Human FTH1, when heterologously expressed in S. cerevisiae, forms higher-order (24-mer) structures visible by electron microscopy and SDS-PAGE, suppresses Bax-induced cell death, and confers resistance to copper-induced cell death, consistent with its iron-storage and antioxidant function.","method":"Heterologous expression in yeast, electron microscopy, cell viability assays with pro-apoptotic stimuli","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — structural validation by EM and functional rescue, but single study, non-mammalian system","pmids":["26886577"],"is_preprint":false},{"year":2018,"finding":"The FTH1 transcript and multiple FTH1 pseudogenes are targeted by oncogenic miRNAs in prostate cancer; pseudogene transcripts act as competing endogenous RNAs (ceRNAs) to sequester these miRNAs and protect FTH1 mRNA; disruption of this ceRNA crosstalk rescues the slow-growth phenotype in vitro and in vivo, and FTH1/pseudogene levels reciprocally regulate intracellular iron.","method":"Unbiased miRNA screen, luciferase reporter assays, in vitro growth assays, xenograft mouse models","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (reporter assay + in vivo rescue), single lab","pmids":["29240947"],"is_preprint":false},{"year":2020,"finding":"Estrogen (E2) silences FTH1 expression in liver cancer cells (Hep-G2, Huh7) via DNA methylation; PRMT5 is recruited to the FTH1 promoter (shown by ChIP), and knockdown of PRMT5, DNMT3B, or estrogen receptor alpha rescues FTH1 from E2-induced silencing; this epigenetic silencing reduces liver cancer cell growth.","method":"ChIP, siRNA knockdown, DNA methylation assays, 5-Aza-2-deoxycytidine demethylation rescue","journal":"Epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms PRMT5 recruitment; multiple knockdown experiments in a single lab","pmids":["32476555"],"is_preprint":false},{"year":2020,"finding":"FTH1 overexpression in PC-12 cells impairs ferritinophagy, downregulates LC3 and NCOA4, and suppresses ferroptotic cell death induced by 6-OHDA; knockdown of FTH1 reduces cell viability and causes mitochondrial dysfunction; ferritinophagy inhibitors chloroquine and bafilomycin A1 block ferritin degradation and ferroptosis, placing FTH1 as a central regulator of the ferritinophagy-ferroptosis cycle.","method":"siRNA knockdown, overexpression, Western blot, pharmacological inhibitors of autophagy, mitochondrial function assays","journal":"Neurotherapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (genetic + pharmacological), single lab","pmids":["32959272"],"is_preprint":false},{"year":2020,"finding":"FTH knockdown in K562 erythroleukemia cells increases ROS, upregulates HIF-1α, which drives CXCR4 expression and CXCL12-mediated cell motility; FTH knockdown also promotes an EMT-like phenotype (increased Snail, Slug, Vimentin; decreased E-cadherin); N-acetylcysteine, AMD3100, or NF-κB inhibition reverses the invasive phenotype, placing FTH at the top of a ROS/HIF-1α/CXCR4/NF-κB axis.","method":"Stable shRNA knockdown, confocal microscopy, cell adhesion and motility assays, pharmacological rescue with NAC/AMD3100/IκB inhibitor","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple pharmacological rescues plus morphological readout, single lab","pmids":["32432042"],"is_preprint":false},{"year":2021,"finding":"Compound 9a directly binds recombinant NCOA4383-522 and disrupts the NCOA4-FTH1 protein-protein interaction, reducing bioavailable intracellular Fe2+ and blocking ferroptosis; this identifies NCOA4 as the molecular target through which ferritinophagy is regulated upstream of FTH1.","method":"Recombinant protein binding assay, protein-protein interaction disruption assay, ferroptosis cell death assay, rat ischemic stroke model","journal":"ACS central science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding to recombinant protein confirmed; interaction disruption validated in cell and in vivo models","pmids":["34235259"],"is_preprint":false},{"year":2021,"finding":"FTH1 overexpression in HCC cells abrogates ferroptosis-inducing anticancer effects, reduces mitochondrial ROS, attenuates impaired mitochondrial respiration, and rescues mitochondrial homeostasis, consistent with FTH1's ferroxidase activity sequestering redox-active Fe2+.","method":"FTH1 overexpression, ROS/lipid peroxide measurement (DCF-DA, C11-BODIPY), Seahorse mitochondrial respiration assay, xenograft in vivo","journal":"Cancer cell international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts in a single lab with in vivo validation","pmids":["34965856"],"is_preprint":false},{"year":2021,"finding":"FTH1 expression is lower in neuroblastoma N2A cells than in normal neural stem cells; ectopic FTH1 expression reduces ROS, reduces ferroptosis-induced cell death, and induces GPX4 expression in N2A cells, establishing FTH1's ferroxidase function as a determinant of ferroptosis sensitivity.","method":"Ectopic FTH1 overexpression, ROS measurement, cell viability assay, GPX4 Western blot","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic rescue with defined molecular readout, single lab single study","pmids":["34445601"],"is_preprint":false},{"year":2021,"finding":"FTH1 silencing in breast cancer cells promotes cell growth and c-MYC expression, reduces chemotherapy sensitivity, and promotes mammosphere formation; conversely, FTH1 overexpression inhibits growth, decreases c-MYC, and sensitizes cells to chemotherapy; silencing c-MYC recapitulates FTH1 overexpression effects, placing FTH1 upstream of c-MYC as a tumor suppressor in breast cancer.","method":"siRNA silencing, overexpression, proliferation assay, mammosphere formation, Western blot for c-MYC","journal":"FEBS open bio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis between FTH1 and c-MYC demonstrated by parallel silencing experiments, single lab","pmids":["34551213"],"is_preprint":false},{"year":2022,"finding":"NSUN5 binds FTH1/FTL mRNA (shown by RNA immunoprecipitation), and NSUN5 depletion reduces 5-methylcytosine (m5C) on FTH1/FTL mRNA, decreases FTH1 protein, increases intracellular iron, and promotes ferroptosis in BMSCs; the recognition of FTH1/FTL by NSUN5 requires TRAP1 recruitment (shown by Co-IP).","method":"RNA immunoprecipitation, Co-immunoprecipitation, m5C methylation assay, FTH1/FTL overexpression/knockdown, ferroptosis markers","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal RNA-protein interaction assays plus functional rescue, single lab","pmids":["35249107"],"is_preprint":false},{"year":2022,"finding":"SIRT6 acts as an upstream regulator of both phosphorylated Nrf2 (which controls GPX4) and NCOA4 (which controls FTH1 ferritinophagy); melatonin inhibits ferroptosis through the SIRT6/NCOA4/FTH1 and SIRT6/p-Nrf2/GPX4 pathways, positioning SIRT6 as a common upstream node.","method":"Genetic engineering knockdown/overexpression of SIRT6 in cells and rats, Western blot, immunofluorescence, ferroptosis markers","journal":"Biomedicine & pharmacotherapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo siRNA model in rats plus in vitro genetic manipulation, single lab","pmids":["36463827"],"is_preprint":false},{"year":2022,"finding":"MAZ (MYC-associated zinc finger protein) transcriptionally activates FTH1 by binding to the FTH1 promoter (confirmed by ChIP assay); lncRNA TUG1 directly targets MAZ (confirmed by luciferase assay); this TUG1/MAZ/FTH1 axis attenuates DHA-induced ferroptosis in glioma cells.","method":"ChIP assay, luciferase assay, FTH1 overexpression/knockdown, in vitro and in vivo ferroptosis assays","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirms direct promoter binding; luciferase reporter validates lncRNA-MAZ interaction; single lab","pmids":["36164395"],"is_preprint":false},{"year":2022,"finding":"NCOA4 binding to FTH1 links ferritin to LC3II in lysosomes to trigger ferritinophagy; caryophyllene oxide promotes ferritinophagy by regulating NCOA4, FTH1, and LC3II levels, resulting in intracellular iron accumulation and ferroptosis in hepatocellular carcinoma cells.","method":"Western blot, immunofluorescence, in vivo tumor model with iron/MDA measurements","journal":"Frontiers in pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — interaction mechanism inferred from expression changes without direct binding assay for this paper","pmids":["35899120"],"is_preprint":false},{"year":2023,"finding":"Heterozygous nonsense variants in FTH1 (especially p.Phe171*) escape nonsense-mediated decay, and patient-derived fibroblasts show elevated ferritin protein levels, increased oxidative stress markers, and increased susceptibility to iron accumulation; C-terminal truncation disrupts the E-helix and 4-fold symmetric pores of the ferritin heteropolymer, likely diminishing iron-storage capacity; the pathogenic mechanism is dominant toxic gain-of-function.","method":"Whole-exome sequencing, patient fibroblast ferritin expression assays, oxidative stress assays, iron accumulation assays, antisense oligonucleotide knockdown rescue","journal":"HGG advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient-derived cellular assays with multiple orthogonal readouts plus ASO rescue, replicated across five unrelated patients","pmids":["37660254"],"is_preprint":false},{"year":2023,"finding":"RSL1D1 RNA-binding protein directly binds the 3' UTR of FTH1 mRNA (shown by RIP assay) and stabilizes it; RSL1D1 knockdown decreases FTH1 expression, elevates intracellular Fe2+, increases MDA, and reduces GPX4, inducing ferroptosis and cellular senescence in colorectal cancer cells.","method":"RNA immunoprecipitation (RIP), siRNA knockdown, Fe2+ measurement, MDA/GPX4 Western blot","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct RIP confirms FTH1 3'-UTR binding; multiple ferroptosis readouts, single lab","pmids":["36913375"],"is_preprint":false},{"year":2023,"finding":"METTL1-mediated m7G methylation of FTH1 mRNA increases FTH1 mRNA expression but suppresses FTH1 translation; METTL1 also promotes maturation of pri-miR-26a via m7G methylation, and the resulting mature miR-26a-5p targets FTH1 mRNA to further reduce FTH1 translation efficiency, thereby promoting ferroptosis and osteosarcoma chemosensitivity.","method":"AlkAniline-Seq for m7G sites, Western blot, qPCR, miRNA overexpression/knockdown, in vivo xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epitranscriptomic profiling combined with functional in vivo validation, single lab","pmids":["38040806"],"is_preprint":false},{"year":2023,"finding":"TFEB transcriptionally inactivates FTH1: PTPRC knockdown promotes TFEB phosphorylation and nuclear translocation, which suppresses FTH1 mRNA expression and promotes ferritinophagy and ferroptosis in osteosarcoma cells; TFEB binding sites on the FTH1 promoter were confirmed by JASPAR prediction and luciferase + ChIP assays.","method":"Luciferase reporter assay, ChIP assay, PTPRC siRNA knockdown, Western blot, immunofluorescence","journal":"Molecular biotechnology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase and ChIP confirm TFEB-FTH1 promoter interaction; genetic epistasis demonstrated, single lab","pmids":["37851191"],"is_preprint":false},{"year":2023,"finding":"AKT1 loss in cisplatin-resistant ovarian cancer cells increases autophagy flux, leading to increased autophagic degradation of FTH1, which reduces ferritin-bound iron stores and increases ferroptosis susceptibility; elevated autophagy (not weakened classical ferroptosis defenses) is the mechanism linking DDP-resistance to ferroptosis vulnerability.","method":"AKT1 knockdown, autophagy flux assays, FTH1 protein measurement, ferroptosis marker assays","journal":"Biochemistry and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic loss-of-function with defined molecular readout, single lab single study","pmids":["37011414"],"is_preprint":false},{"year":2023,"finding":"FTH1 deficiency in myeloid cells reduces DMT1 (iron importer) expression and active phospho-STAT3 in colon tissue; pharmacological STAT3 reactivation restores disease susceptibility in myeloid FTH1-KO mice, placing FTH1 upstream of a DMT1-iron-STAT3 signaling axis in colitis pathogenesis.","method":"Myeloid-specific FTH1 conditional knockout, DSS colitis model, STAT3 inhibitor/activator pharmacology, Western blot","journal":"Inflammatory bowel diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with pharmacological epistasis, single lab","pmids":["36745026"],"is_preprint":false},{"year":2024,"finding":"METTL14 directly targets FTH1 mRNA for m6A methylation, reducing FTH1 mRNA stability and protein expression (validated by luciferase reporter assay and qRT-PCR); this reduction in FTH1 enhances sorafenib-induced ferroptosis in cervical cancer cells in vitro and in vivo.","method":"Luciferase reporter assay, qRT-PCR, siRNA/overexpression, xenograft model","journal":"Cancer biology & therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct reporter assay validates m6A targeting of FTH1; in vivo validation, single lab","pmids":["38738555"],"is_preprint":false},{"year":2024,"finding":"CRYAB (αB-crystallin) physically interacts with FTH1 (shown by IP-MS and Co-IP) and maintains FTH1 protein stability via the proteasome in a lactylation-dependent manner; CRYAB knockdown leads to FTH1 degradation, increased cellular Fe2+ and ROS, ferroptosis, and impaired osteogenic differentiation of BMSCs.","method":"IP-MS, Co-immunoprecipitation, proteasome inhibitor assay, FTH1 overexpression rescue, osteogenic differentiation markers","journal":"Aging","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS and Co-IP confirm interaction; proteasome and lactylation mechanism supported by pharmacological tools, single lab","pmids":["38787373"],"is_preprint":false},{"year":2024,"finding":"NUPR1 transcriptionally promotes FTH1 expression; in HCC, circPIAS1 acts as a ceRNA for miR-455-3p, releasing NUPR1, which then drives FTH1 transcription to enhance iron storage and confer ferroptosis resistance.","method":"RNA immunoprecipitation, luciferase reporter assay, RNA pulldown, FISH, ChIP, Western blot, xenograft","journal":"Molecular cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm NUPR1-FTH1 transcriptional regulation; multiple binding assays for the upstream axis, single lab","pmids":["38802795"],"is_preprint":false},{"year":2024,"finding":"LCN2 (lipocalin-2) interacts with NCOA4 under high-phosphate conditions (shown by co-IP), potentially accelerating FTH1 degradation via ferritinophagy and inducing ferroptosis in VSMCs; LCN2 knockout rescues FTH1 levels and reduces ferroptosis and vascular calcification in CKD mice.","method":"Co-immunoprecipitation, LCN2 knockout mice, LCN2 overexpression, ferroptosis/vascular calcification markers","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP confirms LCN2-NCOA4 interaction; in vivo KO and OE validate functional consequence, single lab","pmids":["39613734"],"is_preprint":false},{"year":2024,"finding":"SMURF1 acts as an E3 ubiquitin ligase for FTH1, facilitating its ubiquitination and degradation; conditional knockout of FTH1 in skeletal muscle causes muscle atrophy, Fe2+ accumulation, GSH depletion, and lipid peroxidation consistent with ferroptosis; SMURF1-mediated FTH1 degradation impedes myoblast differentiation into myotubes.","method":"Co-immunoprecipitation for ubiquitination, conditional knockout of FTH1 in muscle, in vitro myoblast differentiation assay, ferroptosis markers","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic cKO with functional readout; ubiquitination demonstrated by Co-IP; single lab","pmids":["39941157"],"is_preprint":false},{"year":2024,"finding":"FTH1 overexpression reduces chondrocyte susceptibility to ferroptosis and reverses extracellular matrix degradation and SOX9/aggrecan loss after DMM surgery; FTH1 relieves OA by inhibiting the chondrocyte MAPK pathway.","method":"FTH1 siRNA knockdown in chondrocytes, adenovirus FTH1 overexpression in DMM mouse model, Western blot for MAPK pathway, cartilage damage scoring","journal":"BMC musculoskeletal disorders","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo adenoviral overexpression combined with in vitro knockdown; MAPK pathway placement, single lab","pmids":["38609896"],"is_preprint":false},{"year":2024,"finding":"FTO (m6A eraser) demethylates FTH1 mRNA; FTO inhibition increases m6A modification on FTH1 mRNA (confirmed by MeRIP), and both YTHDF1 and YTHDF2 bind FTH1 mRNA (confirmed by RIP) to regulate its expression; loss of FTO reduces FTH1 protein and promotes ferroptosis in spermatogenic cells.","method":"MeRIP assay, RIP assay, FTO knockdown, FTH1 expression measurement, ferroptosis markers","journal":"Free radical biology & medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal RNA-protein interaction assays; direct m6A site on FTH1 confirmed; single lab","pmids":["39848345"],"is_preprint":false},{"year":2024,"finding":"CT-1 (cryptotanshinone derivative) directly targets FTH1 protein, triggering the NCOA4-ferritin interaction and ferritinophagy-mediated ferroptosis in both N2-TANs and TNBC cells; FTH1 is identified as the direct binding target of CT-1.","method":"Target identification assays, FTH1 overexpression rescue, ferroptosis marker assays, in vivo tumor model","journal":"Cell reports. Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target identification with functional overexpression rescue and in vivo validation, single lab","pmids":["39809268"],"is_preprint":false},{"year":2024,"finding":"OTULIN deubiquitinase regulates NCOA4 ubiquitination; OTULIN depletion leads to NCOA4 accumulation, FTH1 degradation (ferritinophagy), and hepatocyte ferroptosis in APAP-induced injury; OTULIN overexpression conversely depletes NCOA4 and accumulates FTH1, protecting against ferroptosis.","method":"OTULIN stable cell lines, ubiquitination assays, Western blot for NCOA4/FTH1, ferroptosis markers in vivo (APAP mouse model)","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deubiquitinase mechanism for NCOA4 upstream of FTH1 shown by genetic manipulation and in vivo model, single lab","pmids":["40158433"],"is_preprint":false},{"year":2025,"finding":"Mechanical tension regulates intracellular free iron via the NCOA4-FTH1 axis: reduced mechanical tension increases FTH1 protein expression and decreases NCOA4, suppressing FTH1 phase separation-driven ferritinophagy and ferroptosis; targeting NCOA4 rescues ferroptosis susceptibility under low mechanical tension.","method":"Mechanical tension manipulation, FTH1 protein expression assay, NCOA4 knockdown, phase separation imaging, ferroptosis marker assays","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and physical manipulation with phase separation imaging; NCOA4-FTH1 axis confirmed; single lab","pmids":["39988734"],"is_preprint":false},{"year":2025,"finding":"Alkbh5 (m6A eraser) demethylates Ythdf1 mRNA, increasing Ythdf1 expression, which then promotes Fth1 translation; Ythdf1 knockdown reverses the anti-ferroptotic effects of Alkbh5 overexpression, placing the Alkbh5-Ythdf1-Fth1 axis as a regulatory pathway inhibiting ferroptosis in cardiomyocytes.","method":"MeRIP assay, RIP assay, Alkbh5/Ythdf1 overexpression/knockdown, Fth1 protein level measurement, ferroptosis markers in H/R cell model and MIRI rat model","journal":"BMC cardiovascular disorders","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis between Alkbh5, Ythdf1, and Fth1 demonstrated by reciprocal knockdown; in vivo rat model validation; single lab","pmids":["40251485"],"is_preprint":false},{"year":2025,"finding":"Nuclear FTH1 associates with BRD2 (not BRD4) in NSCLC cell lines, affecting BRD2 protein stability only in aggressive NSCLC subtypes; FTH1 silencing in JQ1-insensitive cells triggers ferroptosis and downregulates GPX4, SLC7A11, and SLC3A2, revealing a BRD2-FTH1 nuclear functional interaction that suppresses ferroptosis.","method":"Co-immunoprecipitation in a panel of NSCLC cell lines, FTH1 siRNA silencing, ferroptosis marker assays, BRD2/BRD4 protein stability assays","journal":"The FEBS journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP across multiple cell lines; loss-of-function with defined ferroptosis readout; single lab","pmids":["40652527"],"is_preprint":false},{"year":2025,"finding":"DMM (dimethyl malonate) disrupts the NCOA4-FTH1 protein-protein interaction in brain cortex (shown by Co-IP), suppresses NCOA4 and LC3II while upregulating FTH1 and p62, inhibits ferritinophagy and lysosomal Fe2+ accumulation, and protects against ferroptosis in neonatal HIBD; the anti-ferroptotic effects of DMM require FTH1 (reversed by Fth1 knockdown).","method":"Co-immunoprecipitation, Western blot, immunofluorescence (FTH1-LAMP2 colocalization), Fth1 knockdown rescue, neonatal MCAO mouse model","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — Co-IP confirms NCOA4-FTH1 interaction disruption; organelle-level imaging; FTH1-dependent rescue confirmed; in vivo validation","pmids":["40749519"],"is_preprint":false},{"year":2022,"finding":"Neurofilament light chain (NF-L) treatment of microglia triggers secretion of FTH1-containing exosomes; these exosomes induce neuronal membrane lipid peroxidation and neuronal loss; blocking Fth1 expression attenuates this oxidative damage, showing that secreted/exosomal FTH1 can promote ferroptosis-like oxidative damage in a non-cell-autonomous manner.","method":"Microglia-neuron co-culture/conditioned medium, exosome isolation, CKK8 cell death assay, C11-Bodipy lipid peroxidation assay, Fth1 siRNA knockdown","journal":"Oxidative medicine and cellular longevity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — exosome isolation and Fth1 knockdown rescue provide orthogonal evidence; single lab","pmids":["35368870"],"is_preprint":false}],"current_model":"FTH1 encodes the ferroxidase heavy chain subunit of the ferritin heteropolymer; it oxidizes redox-active Fe2+ to Fe3+ for storage, thereby suppressing labile iron-dependent lipid peroxidation and ferroptosis. Its degradation is controlled by ferritinophagy through direct binding to the cargo receptor NCOA4, with NCOA4 ubiquitination regulated by deubiquitinases such as OTULIN, and FTH1 protein stability controlled by E3 ubiquitin ligases (SMURF1) and chaperones (CRYAB via lactylation-dependent proteasomal protection). FTH1 mRNA is post-transcriptionally regulated by multiple RNA-binding proteins (RSL1D1 via 3'-UTR binding, NSUN5/TRAP1 via m5C methylation) and epitranscriptomic writers/erasers (METTL14/METTL1-mediated m6A/m7G reducing stability; FTO/Alkbh5-mediated demethylation stabilizing it via YTHDF1), and transcriptionally regulated by MAZ, NUPR1, TFEB, MBD5/KAT2A, and epigenetically by PRMT5/DNMT3B. FTH1 also localizes to the nucleus where it interacts with BRD2 to suppress ferroptosis-related gene expression. Loss of FTH1 increases ROS, activates HIF-1α/CXCR4/NF-κB signaling promoting EMT-like phenotypes in leukemia cells, and suppresses c-MYC in breast cancer. In neurons, FTH1 can be secreted in exosomes to propagate oxidative damage. Disease-causing C-terminal truncations of FTH1 escape nonsense-mediated decay, elevate ferritin protein, and impair iron-storage capacity via disruption of the 4-fold pores, acting through a dominant toxic gain-of-function mechanism."},"narrative":{"mechanistic_narrative":"FTH1 encodes the ferroxidase heavy-chain subunit of ferritin, which assembles into higher-order 24-mer cages that sequester redox-active iron and thereby restrain ROS production and ferroptotic cell death [PMID:26886577, PMID:34965856, PMID:34445601]. By oxidizing and storing labile Fe2+, FTH1 functions as a central brake on the ferritinophagy–ferroptosis cycle: its turnover is governed by autophagic degradation through direct binding to the cargo receptor NCOA4, and disrupting the NCOA4–FTH1 interaction blocks ferritinophagy and the release of bioavailable iron [PMID:32959272, PMID:34235259, PMID:40749519]. FTH1 protein stability is further set by competing post-translational machinery—the E3 ligase SMURF1 drives its ubiquitination and degradation, while the chaperone CRYAB protects it from proteasomal turnover in a lactylation-dependent manner [PMID:39941157, PMID:38787373]; upstream, deubiquitination of NCOA4 by OTULIN and recruitment by LCN2 tune the rate of ferritinophagic FTH1 loss [PMID:40158433, PMID:39613734]. FTH1 abundance is set transcriptionally by activators including MAZ, NUPR1, and MBD5/KAT2A and repressed by TFEB and by estrogen-driven PRMT5/DNMT3B promoter methylation [PMID:36164395, PMID:38802795, PMID:24750026, PMID:37851191, PMID:32476555], and post-transcriptionally through 3'-UTR binding by RSL1D1 and a dense epitranscriptomic layer in which m6A (METTL14/FTO) and m7G (METTL1) marks, read by YTHDF1, control FTH1 mRNA stability and translation [PMID:36913375, PMID:38738555, PMID:39848345, PMID:38040806]. Through these controls FTH1 sets ferroptosis sensitivity across many cell types, acting as a tumor suppressor upstream of c-MYC in breast cancer and restraining a ROS/HIF-1α/CXCR4/NF-κB invasion axis in leukemia [PMID:34551213, PMID:32432042]. Heterozygous C-terminal nonsense variants (e.g. p.Phe171*) escape nonsense-mediated decay, elevate ferritin protein, disrupt the 4-fold pores, and cause disease through a dominant toxic gain-of-function mechanism [PMID:37660254].","teleology":[{"year":2002,"claim":"Established that an FTH1-derived placental variant (PLIF) carries immunomodulatory activity distinct from canonical iron storage, hinting at functions beyond ferritin assembly.","evidence":"cDNA cloning, immunolocalization, and in vitro lymphocyte proliferation assays from placenta","pmids":["11821435"],"confidence":"Medium","gaps":["PLIF is a C-terminally substituted variant, not full-length FTH1","mechanism of lymphocyte suppression not resolved"]},{"year":2003,"claim":"Dissected the signaling route by which the FTH1-derived C48 domain elicits IL-10, defining a calcium/calmodulin-p38 MAPK pathway.","evidence":"Cytokine ELISA with calmodulin and p38 inhibitors in monocytes","pmids":["12670872"],"confidence":"Medium","gaps":["pertains to the PLIF variant rather than canonical FTH1","receptor for C48 unidentified"]},{"year":2011,"claim":"Showed FTH1 has a direct protein-interaction role in apoptosis control by binding Daxx and suppressing Fas-Daxx-ASK1-JNK1 signaling, beyond its iron-storage function.","evidence":"Yeast two-hybrid, GST pull-down, Co-IP, and JNK pathway assays","pmids":["21573799"],"confidence":"Medium","gaps":["interaction interface not mapped","physiological relevance in vivo untested"]},{"year":2014,"claim":"Defined transcriptional control of Fth1 in vivo, showing MBD5 enhances Fth1 transcription via KAT2A-dependent histone acetylation to prevent iron overload.","evidence":"Conditional knockout mice, luciferase promoter assay, histone acetylation analysis","pmids":["24750026"],"confidence":"High","gaps":["direct MBD5 promoter occupancy not shown","tissue specificity beyond intestine unaddressed"]},{"year":2016,"claim":"Confirmed that human FTH1 self-assembles into 24-mer cages and confers cytoprotection against pro-death and metal stress, validating its core antioxidant/storage role.","evidence":"Heterologous expression in yeast, EM, viability assays","pmids":["26886577"],"confidence":"Medium","gaps":["non-mammalian system","ferroxidase kinetics not measured"]},{"year":2020,"claim":"Placed FTH1 as a central node of the ferritinophagy-ferroptosis cycle, where its overexpression impairs NCOA4-dependent ferritin degradation and suppresses ferroptosis.","evidence":"siRNA/overexpression, autophagy inhibitors, mitochondrial assays in PC-12 cells","pmids":["32959272"],"confidence":"Medium","gaps":["direct FTH1-NCOA4 binding not assayed in this study","single neuronal cell line"]},{"year":2020,"claim":"Linked FTH1 loss to a pro-invasive program, showing FTH knockdown raises ROS and drives a HIF-1α/CXCR4/NF-κB EMT-like axis in leukemia.","evidence":"Stable shRNA, motility assays, pharmacological rescue (NAC/AMD3100/IκB inhibitor)","pmids":["32432042"],"confidence":"Medium","gaps":["axis correlative downstream of ROS","single cell line"]},{"year":2020,"claim":"Demonstrated epigenetic silencing of FTH1 by estrogen via PRMT5-dependent DNA methylation, connecting hormonal signaling to ferritin levels in liver cancer.","evidence":"ChIP, siRNA knockdown, methylation and demethylation rescue","pmids":["32476555"],"confidence":"Medium","gaps":["direct DNMT3B-PRMT5 cooperation mechanism not resolved","single tumor type"]},{"year":2021,"claim":"Pinpointed NCOA4 as the druggable interaction target upstream of FTH1, with a small molecule directly disrupting NCOA4-FTH1 binding to block ferritinophagy and ferroptosis.","evidence":"Recombinant protein binding, PPI disruption, ferroptosis and stroke models","pmids":["34235259"],"confidence":"High","gaps":["binding interface residues not mapped","selectivity of the compound beyond NCOA4 untested"]},{"year":2021,"claim":"Confirmed FTH1 ferroxidase function determines ferroptosis sensitivity across tumor contexts, with overexpression reducing ROS and inducing GPX4 while abrogating ferroptosis-based therapy.","evidence":"Overexpression, ROS/lipid peroxide measurement, Seahorse, GPX4 blots, xenografts","pmids":["34965856","34445601"],"confidence":"Medium","gaps":["mechanistic link between FTH1 and GPX4 induction unresolved","correlative in single labs"]},{"year":2021,"claim":"Established FTH1 as a tumor suppressor upstream of c-MYC in breast cancer through epistasis between FTH1 and c-MYC manipulation.","evidence":"siRNA/overexpression, proliferation, mammosphere, c-MYC blots","pmids":["34551213"],"confidence":"Medium","gaps":["mechanism linking FTH1 to c-MYC not defined","single cancer type"]},{"year":2018,"claim":"Revealed a ceRNA layer controlling FTH1, where FTH1 pseudogenes sponge oncogenic miRNAs to protect FTH1 mRNA and regulate intracellular iron.","evidence":"miRNA screen, luciferase reporters, growth assays, xenografts","pmids":["29240947"],"confidence":"Medium","gaps":["relative contribution of individual pseudogenes unclear","single cancer type"]},{"year":2022,"claim":"Uncovered an m5C methylation mechanism for FTH1/FTL mRNA, with NSUN5 (aided by TRAP1) marking the transcripts to sustain FTH1 protein and restrain ferroptosis.","evidence":"RIP, Co-IP, m5C assays, overexpression/knockdown in BMSCs","pmids":["35249107"],"confidence":"Medium","gaps":["m5C reader for FTH1 not identified","single cell system"]},{"year":2022,"claim":"Identified MAZ as a direct transcriptional activator of FTH1 within a lncRNA TUG1/MAZ/FTH1 axis modulating ferroptosis in glioma.","evidence":"ChIP, luciferase, overexpression/knockdown, in vivo ferroptosis assays","pmids":["36164395"],"confidence":"Medium","gaps":["other MAZ target contributions not excluded","single tumor type"]},{"year":2022,"claim":"Positioned SIRT6 as a common upstream node coordinating both NCOA4/FTH1 ferritinophagy and Nrf2/GPX4 arms of ferroptosis defense.","evidence":"SIRT6 knockdown/overexpression in cells and rats, ferroptosis markers","pmids":["36463827"],"confidence":"Medium","gaps":["direct SIRT6 targets in these arms not defined","correlative pathway placement"]},{"year":2022,"claim":"Extended FTH1 biology to non-cell-autonomous damage, showing microglia secrete FTH1-containing exosomes that promote neuronal lipid peroxidation.","evidence":"Conditioned medium/exosome isolation, lipid peroxidation assays, Fth1 knockdown","pmids":["35368870"],"confidence":"Medium","gaps":["mechanism of FTH1 loading into exosomes unknown","redox role of secreted FTH1 not biochemically defined"]},{"year":2023,"claim":"Defined a Mendelian disease mechanism: C-terminal FTH1 nonsense variants escape NMD, disrupt the 4-fold pores, and cause a dominant toxic gain-of-function with elevated ferritin and oxidative stress.","evidence":"Exome sequencing, patient fibroblast assays, ASO knockdown rescue across five patients","pmids":["37660254"],"confidence":"High","gaps":["organ-level pathophysiology in patients not fully characterized","structural pore disruption inferred, not solved structurally"]},{"year":2023,"claim":"Identified RSL1D1 as a 3'-UTR-binding stabilizer of FTH1 mRNA linking FTH1 abundance to ferroptosis and senescence.","evidence":"RIP, siRNA knockdown, Fe2+/MDA/GPX4 readouts in colorectal cancer","pmids":["36913375"],"confidence":"Medium","gaps":["RSL1D1 binding motif on FTH1 UTR not mapped","single cancer type"]},{"year":2023,"claim":"Resolved m7G control of FTH1, where METTL1 raises FTH1 mRNA but suppresses its translation and matures a miR-26a that further represses FTH1 to promote ferroptosis.","evidence":"AlkAniline-Seq, blots, miRNA manipulation, xenograft","pmids":["38040806"],"confidence":"Medium","gaps":["mechanism of translation suppression by m7G not fully defined","single tumor type"]},{"year":2023,"claim":"Established TFEB as a direct transcriptional repressor of FTH1 that drives ferritinophagy downstream of PTPRC loss.","evidence":"Luciferase, ChIP, siRNA knockdown in osteosarcoma","pmids":["37851191"],"confidence":"Medium","gaps":["TFEB direct vs autophagy-program-mediated effect not fully separated","single tumor type"]},{"year":2023,"claim":"Showed autophagic FTH1 degradation underlies a therapeutic vulnerability, with AKT1 loss raising autophagy flux to deplete FTH1 and sensitize resistant ovarian cancer to ferroptosis.","evidence":"AKT1 knockdown, autophagy flux and FTH1 protein assays","pmids":["37011414"],"confidence":"Medium","gaps":["NCOA4-dependence not directly tested here","single resistance model"]},{"year":2023,"claim":"Connected myeloid FTH1 to inflammatory signaling, placing it upstream of a DMT1-iron-STAT3 axis in colitis.","evidence":"Myeloid-specific FTH1 cKO, DSS colitis, STAT3 pharmacology","pmids":["36745026"],"confidence":"Medium","gaps":["mechanistic link from FTH1 to DMT1 unresolved","ferroptosis contribution not isolated"]},{"year":2024,"claim":"Defined opposing epitranscriptomic regulators of FTH1: METTL14-deposited m6A destabilizes FTH1 mRNA, while FTO erases m6A and YTHDF1/2 read it to control FTH1 expression and ferroptosis.","evidence":"Luciferase/qRT-PCR (METTL14) and MeRIP/RIP (FTO, YTHDF1/2) with functional assays","pmids":["38738555","39848345"],"confidence":"Medium","gaps":["context-dependence of reader outcome (stability vs translation) not reconciled","single tissue per study"]},{"year":2024,"claim":"Defined post-translational protein-stability control of FTH1 by competing machinery: CRYAB protects FTH1 from proteasomal degradation via lactylation, while SMURF1 ubiquitinates FTH1 for degradation, governing ferroptosis and differentiation.","evidence":"IP-MS/Co-IP, proteasome inhibitors (CRYAB); Co-IP ubiquitination and muscle cKO (SMURF1)","pmids":["38787373","39941157"],"confidence":"Medium","gaps":["ubiquitination sites on FTH1 not mapped","interplay between CRYAB and SMURF1 not tested together"]},{"year":2024,"claim":"Identified NUPR1 as a direct transcriptional activator of FTH1 conferring ferroptosis resistance via a circPIAS1/miR-455-3p/NUPR1 axis in HCC.","evidence":"RIP, luciferase, RNA pulldown, FISH, ChIP, xenograft","pmids":["38802795"],"confidence":"Medium","gaps":["NUPR1 promoter binding site on FTH1 not detailed","single cancer type"]},{"year":2024,"claim":"Extended upstream control of ferritinophagy to LCN2, which interacts with NCOA4 under high phosphate to accelerate FTH1 degradation and ferroptosis in vascular calcification.","evidence":"Co-IP, LCN2 KO/OE mice, ferroptosis/calcification markers","pmids":["39613734"],"confidence":"Medium","gaps":["LCN2 effect on NCOA4-FTH1 binding is indirect/inferred","phosphate-dependence mechanism unclear"]},{"year":2024,"claim":"Showed FTH1 protects cartilage by limiting ferroptosis and suppressing MAPK signaling in osteoarthritis.","evidence":"Chondrocyte knockdown, adenoviral overexpression in DMM model, MAPK blots","pmids":["38609896"],"confidence":"Medium","gaps":["mechanistic link from FTH1 to MAPK unresolved","single disease model"]},{"year":2024,"claim":"Validated FTH1 as a direct druggable protein target, with CT-1 binding FTH1 to trigger NCOA4-mediated ferritinophagy and ferroptosis in tumors.","evidence":"Target identification, overexpression rescue, in vivo tumor model","pmids":["39809268"],"confidence":"Medium","gaps":["binding site on FTH1 not mapped","selectivity not fully profiled"]},{"year":2025,"claim":"Implicated OTULIN deubiquitination of NCOA4 as a control point that indirectly sets FTH1 levels and hepatocyte ferroptosis.","evidence":"OTULIN stable lines, ubiquitination assays, APAP mouse model","pmids":["40158433"],"confidence":"Medium","gaps":["direct OTULIN-NCOA4 enzymology not fully characterized","single injury model"]},{"year":2025,"claim":"Connected mechanical tension to iron handling via FTH1 phase separation, showing low tension raises FTH1 and suppresses NCOA4-driven ferritinophagy and ferroptosis.","evidence":"Tension manipulation, NCOA4 knockdown, phase separation imaging","pmids":["39988734"],"confidence":"Medium","gaps":["molecular sensor coupling tension to NCOA4 unidentified","physiological generality unclear"]},{"year":2025,"claim":"Added a further epitranscriptomic relay, the Alkbh5-Ythdf1-Fth1 axis, promoting FTH1 translation to inhibit cardiomyocyte ferroptosis.","evidence":"MeRIP, RIP, reciprocal knockdown, H/R and MIRI rat models","pmids":["40251485"],"confidence":"Medium","gaps":["direct vs Ythdf1-mediated FTH1 regulation by Alkbh5 not separated","single disease context"]},{"year":2025,"claim":"Revealed a nuclear function for FTH1, where it associates with BRD2 to support its stability and suppress ferroptosis-related gene expression in aggressive NSCLC.","evidence":"Co-IP across NSCLC cell lines, siRNA silencing, ferroptosis markers","pmids":["40652527"],"confidence":"Medium","gaps":["nuclear import mechanism of FTH1 unknown","interaction specificity to BRD2 vs BRD4 mechanistically unexplained"]},{"year":2025,"claim":"Provided strong validation of NCOA4-FTH1 disruption as a neuroprotective strategy, showing DMM blocks the interaction, inhibits ferritinophagy, and protects in an FTH1-dependent manner.","evidence":"Co-IP, FTH1-LAMP2 imaging, Fth1 knockdown rescue, neonatal MCAO model","pmids":["40749519"],"confidence":"High","gaps":["DMM target specificity beyond the NCOA4-FTH1 interaction not fully resolved"]},{"year":null,"claim":"How the dense, partly redundant regulatory layers (transcriptional, epitranscriptomic, ubiquitin/chaperone, and ferritinophagic) are integrated in a single cell to set FTH1 levels, and how nuclear/secreted FTH1 pools relate mechanistically to the cytosolic iron-storage cage, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no unified model reconciling 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unlike FTH1, PLIF mRNA lacks the iron response element in the 5'-UTR, indicating iron-independent synthesis; PLIF localizes to syncytiotrophoblasts at the fetal-maternal interface and inhibits peripheral blood mononuclear cell proliferation and mixed lymphocyte reactions in vitro.\",\n      \"method\": \"cDNA cloning, immunolocalization, in vitro lymphocyte proliferation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cloning and functional in vitro assays in a single study; localization confirmed by immunostaining\",\n      \"pmids\": [\"11821435\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The C48 domain of PLIF (the FTH1-derived immunomodulatory ferritin) induces IL-10 production in monocytes through a calcium/calmodulin-p38 MAP kinase signaling pathway; ERK1/2, also activated by C48, exerts a limiting effect on IL-10 production.\",\n      \"method\": \"Cytokine ELISA, pharmacological inhibitors of calmodulin and p38 MAPK\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissected with multiple pharmacological tools in a single lab\",\n      \"pmids\": [\"12670872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FTH1 physically interacts with the apoptosis regulator Daxx, as demonstrated by yeast two-hybrid screening, GST pull-down, and co-immunoprecipitation; FTH1 inhibits Daxx-mediated apoptosis by suppressing activation of the Fas-Daxx-ASK1-JNK1 signaling pathway.\",\n      \"method\": \"Yeast two-hybrid, GST pull-down, co-immunoprecipitation, JNK pathway activity assays\",\n      \"journal\": \"Molecular biology reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three orthogonal binding methods plus functional apoptosis readout in a single study\",\n      \"pmids\": [\"21573799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MBD5 regulates Fth1 transcription in the intestine through the histone acetyltransferase KAT2A: MBD5 deletion reduces histone H4 acetylation at the Fth1 promoter, decreases intestinal Fth1 mRNA, and causes iron overload in mice; Fth1 promoter-reporter assays show MBD5 enhances Fth1 transcription in a dose-dependent manner.\",\n      \"method\": \"Conditional knockout mice, luciferase promoter assay, chromatin histone acetylation analysis, serum/liver iron measurements\",\n      \"journal\": \"British journal of haematology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vivo genetic model corroborated by promoter-reporter assay and ChIP-level histone acetylation data\",\n      \"pmids\": [\"24750026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Human FTH1, when heterologously expressed in S. cerevisiae, forms higher-order (24-mer) structures visible by electron microscopy and SDS-PAGE, suppresses Bax-induced cell death, and confers resistance to copper-induced cell death, consistent with its iron-storage and antioxidant function.\",\n      \"method\": \"Heterologous expression in yeast, electron microscopy, cell viability assays with pro-apoptotic stimuli\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — structural validation by EM and functional rescue, but single study, non-mammalian system\",\n      \"pmids\": [\"26886577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The FTH1 transcript and multiple FTH1 pseudogenes are targeted by oncogenic miRNAs in prostate cancer; pseudogene transcripts act as competing endogenous RNAs (ceRNAs) to sequester these miRNAs and protect FTH1 mRNA; disruption of this ceRNA crosstalk rescues the slow-growth phenotype in vitro and in vivo, and FTH1/pseudogene levels reciprocally regulate intracellular iron.\",\n      \"method\": \"Unbiased miRNA screen, luciferase reporter assays, in vitro growth assays, xenograft mouse models\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (reporter assay + in vivo rescue), single lab\",\n      \"pmids\": [\"29240947\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Estrogen (E2) silences FTH1 expression in liver cancer cells (Hep-G2, Huh7) via DNA methylation; PRMT5 is recruited to the FTH1 promoter (shown by ChIP), and knockdown of PRMT5, DNMT3B, or estrogen receptor alpha rescues FTH1 from E2-induced silencing; this epigenetic silencing reduces liver cancer cell growth.\",\n      \"method\": \"ChIP, siRNA knockdown, DNA methylation assays, 5-Aza-2-deoxycytidine demethylation rescue\",\n      \"journal\": \"Epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms PRMT5 recruitment; multiple knockdown experiments in a single lab\",\n      \"pmids\": [\"32476555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FTH1 overexpression in PC-12 cells impairs ferritinophagy, downregulates LC3 and NCOA4, and suppresses ferroptotic cell death induced by 6-OHDA; knockdown of FTH1 reduces cell viability and causes mitochondrial dysfunction; ferritinophagy inhibitors chloroquine and bafilomycin A1 block ferritin degradation and ferroptosis, placing FTH1 as a central regulator of the ferritinophagy-ferroptosis cycle.\",\n      \"method\": \"siRNA knockdown, overexpression, Western blot, pharmacological inhibitors of autophagy, mitochondrial function assays\",\n      \"journal\": \"Neurotherapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (genetic + pharmacological), single lab\",\n      \"pmids\": [\"32959272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"FTH knockdown in K562 erythroleukemia cells increases ROS, upregulates HIF-1α, which drives CXCR4 expression and CXCL12-mediated cell motility; FTH knockdown also promotes an EMT-like phenotype (increased Snail, Slug, Vimentin; decreased E-cadherin); N-acetylcysteine, AMD3100, or NF-κB inhibition reverses the invasive phenotype, placing FTH at the top of a ROS/HIF-1α/CXCR4/NF-κB axis.\",\n      \"method\": \"Stable shRNA knockdown, confocal microscopy, cell adhesion and motility assays, pharmacological rescue with NAC/AMD3100/IκB inhibitor\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple pharmacological rescues plus morphological readout, single lab\",\n      \"pmids\": [\"32432042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Compound 9a directly binds recombinant NCOA4383-522 and disrupts the NCOA4-FTH1 protein-protein interaction, reducing bioavailable intracellular Fe2+ and blocking ferroptosis; this identifies NCOA4 as the molecular target through which ferritinophagy is regulated upstream of FTH1.\",\n      \"method\": \"Recombinant protein binding assay, protein-protein interaction disruption assay, ferroptosis cell death assay, rat ischemic stroke model\",\n      \"journal\": \"ACS central science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding to recombinant protein confirmed; interaction disruption validated in cell and in vivo models\",\n      \"pmids\": [\"34235259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FTH1 overexpression in HCC cells abrogates ferroptosis-inducing anticancer effects, reduces mitochondrial ROS, attenuates impaired mitochondrial respiration, and rescues mitochondrial homeostasis, consistent with FTH1's ferroxidase activity sequestering redox-active Fe2+.\",\n      \"method\": \"FTH1 overexpression, ROS/lipid peroxide measurement (DCF-DA, C11-BODIPY), Seahorse mitochondrial respiration assay, xenograft in vivo\",\n      \"journal\": \"Cancer cell international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts in a single lab with in vivo validation\",\n      \"pmids\": [\"34965856\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FTH1 expression is lower in neuroblastoma N2A cells than in normal neural stem cells; ectopic FTH1 expression reduces ROS, reduces ferroptosis-induced cell death, and induces GPX4 expression in N2A cells, establishing FTH1's ferroxidase function as a determinant of ferroptosis sensitivity.\",\n      \"method\": \"Ectopic FTH1 overexpression, ROS measurement, cell viability assay, GPX4 Western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic rescue with defined molecular readout, single lab single study\",\n      \"pmids\": [\"34445601\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FTH1 silencing in breast cancer cells promotes cell growth and c-MYC expression, reduces chemotherapy sensitivity, and promotes mammosphere formation; conversely, FTH1 overexpression inhibits growth, decreases c-MYC, and sensitizes cells to chemotherapy; silencing c-MYC recapitulates FTH1 overexpression effects, placing FTH1 upstream of c-MYC as a tumor suppressor in breast cancer.\",\n      \"method\": \"siRNA silencing, overexpression, proliferation assay, mammosphere formation, Western blot for c-MYC\",\n      \"journal\": \"FEBS open bio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis between FTH1 and c-MYC demonstrated by parallel silencing experiments, single lab\",\n      \"pmids\": [\"34551213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NSUN5 binds FTH1/FTL mRNA (shown by RNA immunoprecipitation), and NSUN5 depletion reduces 5-methylcytosine (m5C) on FTH1/FTL mRNA, decreases FTH1 protein, increases intracellular iron, and promotes ferroptosis in BMSCs; the recognition of FTH1/FTL by NSUN5 requires TRAP1 recruitment (shown by Co-IP).\",\n      \"method\": \"RNA immunoprecipitation, Co-immunoprecipitation, m5C methylation assay, FTH1/FTL overexpression/knockdown, ferroptosis markers\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal RNA-protein interaction assays plus functional rescue, single lab\",\n      \"pmids\": [\"35249107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SIRT6 acts as an upstream regulator of both phosphorylated Nrf2 (which controls GPX4) and NCOA4 (which controls FTH1 ferritinophagy); melatonin inhibits ferroptosis through the SIRT6/NCOA4/FTH1 and SIRT6/p-Nrf2/GPX4 pathways, positioning SIRT6 as a common upstream node.\",\n      \"method\": \"Genetic engineering knockdown/overexpression of SIRT6 in cells and rats, Western blot, immunofluorescence, ferroptosis markers\",\n      \"journal\": \"Biomedicine & pharmacotherapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo siRNA model in rats plus in vitro genetic manipulation, single lab\",\n      \"pmids\": [\"36463827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MAZ (MYC-associated zinc finger protein) transcriptionally activates FTH1 by binding to the FTH1 promoter (confirmed by ChIP assay); lncRNA TUG1 directly targets MAZ (confirmed by luciferase assay); this TUG1/MAZ/FTH1 axis attenuates DHA-induced ferroptosis in glioma cells.\",\n      \"method\": \"ChIP assay, luciferase assay, FTH1 overexpression/knockdown, in vitro and in vivo ferroptosis assays\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirms direct promoter binding; luciferase reporter validates lncRNA-MAZ interaction; single lab\",\n      \"pmids\": [\"36164395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NCOA4 binding to FTH1 links ferritin to LC3II in lysosomes to trigger ferritinophagy; caryophyllene oxide promotes ferritinophagy by regulating NCOA4, FTH1, and LC3II levels, resulting in intracellular iron accumulation and ferroptosis in hepatocellular carcinoma cells.\",\n      \"method\": \"Western blot, immunofluorescence, in vivo tumor model with iron/MDA measurements\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — interaction mechanism inferred from expression changes without direct binding assay for this paper\",\n      \"pmids\": [\"35899120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Heterozygous nonsense variants in FTH1 (especially p.Phe171*) escape nonsense-mediated decay, and patient-derived fibroblasts show elevated ferritin protein levels, increased oxidative stress markers, and increased susceptibility to iron accumulation; C-terminal truncation disrupts the E-helix and 4-fold symmetric pores of the ferritin heteropolymer, likely diminishing iron-storage capacity; the pathogenic mechanism is dominant toxic gain-of-function.\",\n      \"method\": \"Whole-exome sequencing, patient fibroblast ferritin expression assays, oxidative stress assays, iron accumulation assays, antisense oligonucleotide knockdown rescue\",\n      \"journal\": \"HGG advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient-derived cellular assays with multiple orthogonal readouts plus ASO rescue, replicated across five unrelated patients\",\n      \"pmids\": [\"37660254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"RSL1D1 RNA-binding protein directly binds the 3' UTR of FTH1 mRNA (shown by RIP assay) and stabilizes it; RSL1D1 knockdown decreases FTH1 expression, elevates intracellular Fe2+, increases MDA, and reduces GPX4, inducing ferroptosis and cellular senescence in colorectal cancer cells.\",\n      \"method\": \"RNA immunoprecipitation (RIP), siRNA knockdown, Fe2+ measurement, MDA/GPX4 Western blot\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct RIP confirms FTH1 3'-UTR binding; multiple ferroptosis readouts, single lab\",\n      \"pmids\": [\"36913375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"METTL1-mediated m7G methylation of FTH1 mRNA increases FTH1 mRNA expression but suppresses FTH1 translation; METTL1 also promotes maturation of pri-miR-26a via m7G methylation, and the resulting mature miR-26a-5p targets FTH1 mRNA to further reduce FTH1 translation efficiency, thereby promoting ferroptosis and osteosarcoma chemosensitivity.\",\n      \"method\": \"AlkAniline-Seq for m7G sites, Western blot, qPCR, miRNA overexpression/knockdown, in vivo xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epitranscriptomic profiling combined with functional in vivo validation, single lab\",\n      \"pmids\": [\"38040806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TFEB transcriptionally inactivates FTH1: PTPRC knockdown promotes TFEB phosphorylation and nuclear translocation, which suppresses FTH1 mRNA expression and promotes ferritinophagy and ferroptosis in osteosarcoma cells; TFEB binding sites on the FTH1 promoter were confirmed by JASPAR prediction and luciferase + ChIP assays.\",\n      \"method\": \"Luciferase reporter assay, ChIP assay, PTPRC siRNA knockdown, Western blot, immunofluorescence\",\n      \"journal\": \"Molecular biotechnology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase and ChIP confirm TFEB-FTH1 promoter interaction; genetic epistasis demonstrated, single lab\",\n      \"pmids\": [\"37851191\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"AKT1 loss in cisplatin-resistant ovarian cancer cells increases autophagy flux, leading to increased autophagic degradation of FTH1, which reduces ferritin-bound iron stores and increases ferroptosis susceptibility; elevated autophagy (not weakened classical ferroptosis defenses) is the mechanism linking DDP-resistance to ferroptosis vulnerability.\",\n      \"method\": \"AKT1 knockdown, autophagy flux assays, FTH1 protein measurement, ferroptosis marker assays\",\n      \"journal\": \"Biochemistry and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic loss-of-function with defined molecular readout, single lab single study\",\n      \"pmids\": [\"37011414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FTH1 deficiency in myeloid cells reduces DMT1 (iron importer) expression and active phospho-STAT3 in colon tissue; pharmacological STAT3 reactivation restores disease susceptibility in myeloid FTH1-KO mice, placing FTH1 upstream of a DMT1-iron-STAT3 signaling axis in colitis pathogenesis.\",\n      \"method\": \"Myeloid-specific FTH1 conditional knockout, DSS colitis model, STAT3 inhibitor/activator pharmacology, Western blot\",\n      \"journal\": \"Inflammatory bowel diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with pharmacological epistasis, single lab\",\n      \"pmids\": [\"36745026\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"METTL14 directly targets FTH1 mRNA for m6A methylation, reducing FTH1 mRNA stability and protein expression (validated by luciferase reporter assay and qRT-PCR); this reduction in FTH1 enhances sorafenib-induced ferroptosis in cervical cancer cells in vitro and in vivo.\",\n      \"method\": \"Luciferase reporter assay, qRT-PCR, siRNA/overexpression, xenograft model\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct reporter assay validates m6A targeting of FTH1; in vivo validation, single lab\",\n      \"pmids\": [\"38738555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CRYAB (αB-crystallin) physically interacts with FTH1 (shown by IP-MS and Co-IP) and maintains FTH1 protein stability via the proteasome in a lactylation-dependent manner; CRYAB knockdown leads to FTH1 degradation, increased cellular Fe2+ and ROS, ferroptosis, and impaired osteogenic differentiation of BMSCs.\",\n      \"method\": \"IP-MS, Co-immunoprecipitation, proteasome inhibitor assay, FTH1 overexpression rescue, osteogenic differentiation markers\",\n      \"journal\": \"Aging\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS and Co-IP confirm interaction; proteasome and lactylation mechanism supported by pharmacological tools, single lab\",\n      \"pmids\": [\"38787373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NUPR1 transcriptionally promotes FTH1 expression; in HCC, circPIAS1 acts as a ceRNA for miR-455-3p, releasing NUPR1, which then drives FTH1 transcription to enhance iron storage and confer ferroptosis resistance.\",\n      \"method\": \"RNA immunoprecipitation, luciferase reporter assay, RNA pulldown, FISH, ChIP, Western blot, xenograft\",\n      \"journal\": \"Molecular cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm NUPR1-FTH1 transcriptional regulation; multiple binding assays for the upstream axis, single lab\",\n      \"pmids\": [\"38802795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LCN2 (lipocalin-2) interacts with NCOA4 under high-phosphate conditions (shown by co-IP), potentially accelerating FTH1 degradation via ferritinophagy and inducing ferroptosis in VSMCs; LCN2 knockout rescues FTH1 levels and reduces ferroptosis and vascular calcification in CKD mice.\",\n      \"method\": \"Co-immunoprecipitation, LCN2 knockout mice, LCN2 overexpression, ferroptosis/vascular calcification markers\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP confirms LCN2-NCOA4 interaction; in vivo KO and OE validate functional consequence, single lab\",\n      \"pmids\": [\"39613734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SMURF1 acts as an E3 ubiquitin ligase for FTH1, facilitating its ubiquitination and degradation; conditional knockout of FTH1 in skeletal muscle causes muscle atrophy, Fe2+ accumulation, GSH depletion, and lipid peroxidation consistent with ferroptosis; SMURF1-mediated FTH1 degradation impedes myoblast differentiation into myotubes.\",\n      \"method\": \"Co-immunoprecipitation for ubiquitination, conditional knockout of FTH1 in muscle, in vitro myoblast differentiation assay, ferroptosis markers\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic cKO with functional readout; ubiquitination demonstrated by Co-IP; single lab\",\n      \"pmids\": [\"39941157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTH1 overexpression reduces chondrocyte susceptibility to ferroptosis and reverses extracellular matrix degradation and SOX9/aggrecan loss after DMM surgery; FTH1 relieves OA by inhibiting the chondrocyte MAPK pathway.\",\n      \"method\": \"FTH1 siRNA knockdown in chondrocytes, adenovirus FTH1 overexpression in DMM mouse model, Western blot for MAPK pathway, cartilage damage scoring\",\n      \"journal\": \"BMC musculoskeletal disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo adenoviral overexpression combined with in vitro knockdown; MAPK pathway placement, single lab\",\n      \"pmids\": [\"38609896\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTO (m6A eraser) demethylates FTH1 mRNA; FTO inhibition increases m6A modification on FTH1 mRNA (confirmed by MeRIP), and both YTHDF1 and YTHDF2 bind FTH1 mRNA (confirmed by RIP) to regulate its expression; loss of FTO reduces FTH1 protein and promotes ferroptosis in spermatogenic cells.\",\n      \"method\": \"MeRIP assay, RIP assay, FTO knockdown, FTH1 expression measurement, ferroptosis markers\",\n      \"journal\": \"Free radical biology & medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal RNA-protein interaction assays; direct m6A site on FTH1 confirmed; single lab\",\n      \"pmids\": [\"39848345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CT-1 (cryptotanshinone derivative) directly targets FTH1 protein, triggering the NCOA4-ferritin interaction and ferritinophagy-mediated ferroptosis in both N2-TANs and TNBC cells; FTH1 is identified as the direct binding target of CT-1.\",\n      \"method\": \"Target identification assays, FTH1 overexpression rescue, ferroptosis marker assays, in vivo tumor model\",\n      \"journal\": \"Cell reports. Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target identification with functional overexpression rescue and in vivo validation, single lab\",\n      \"pmids\": [\"39809268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"OTULIN deubiquitinase regulates NCOA4 ubiquitination; OTULIN depletion leads to NCOA4 accumulation, FTH1 degradation (ferritinophagy), and hepatocyte ferroptosis in APAP-induced injury; OTULIN overexpression conversely depletes NCOA4 and accumulates FTH1, protecting against ferroptosis.\",\n      \"method\": \"OTULIN stable cell lines, ubiquitination assays, Western blot for NCOA4/FTH1, ferroptosis markers in vivo (APAP mouse model)\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deubiquitinase mechanism for NCOA4 upstream of FTH1 shown by genetic manipulation and in vivo model, single lab\",\n      \"pmids\": [\"40158433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Mechanical tension regulates intracellular free iron via the NCOA4-FTH1 axis: reduced mechanical tension increases FTH1 protein expression and decreases NCOA4, suppressing FTH1 phase separation-driven ferritinophagy and ferroptosis; targeting NCOA4 rescues ferroptosis susceptibility under low mechanical tension.\",\n      \"method\": \"Mechanical tension manipulation, FTH1 protein expression assay, NCOA4 knockdown, phase separation imaging, ferroptosis marker assays\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and physical manipulation with phase separation imaging; NCOA4-FTH1 axis confirmed; single lab\",\n      \"pmids\": [\"39988734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Alkbh5 (m6A eraser) demethylates Ythdf1 mRNA, increasing Ythdf1 expression, which then promotes Fth1 translation; Ythdf1 knockdown reverses the anti-ferroptotic effects of Alkbh5 overexpression, placing the Alkbh5-Ythdf1-Fth1 axis as a regulatory pathway inhibiting ferroptosis in cardiomyocytes.\",\n      \"method\": \"MeRIP assay, RIP assay, Alkbh5/Ythdf1 overexpression/knockdown, Fth1 protein level measurement, ferroptosis markers in H/R cell model and MIRI rat model\",\n      \"journal\": \"BMC cardiovascular disorders\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis between Alkbh5, Ythdf1, and Fth1 demonstrated by reciprocal knockdown; in vivo rat model validation; single lab\",\n      \"pmids\": [\"40251485\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nuclear FTH1 associates with BRD2 (not BRD4) in NSCLC cell lines, affecting BRD2 protein stability only in aggressive NSCLC subtypes; FTH1 silencing in JQ1-insensitive cells triggers ferroptosis and downregulates GPX4, SLC7A11, and SLC3A2, revealing a BRD2-FTH1 nuclear functional interaction that suppresses ferroptosis.\",\n      \"method\": \"Co-immunoprecipitation in a panel of NSCLC cell lines, FTH1 siRNA silencing, ferroptosis marker assays, BRD2/BRD4 protein stability assays\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP across multiple cell lines; loss-of-function with defined ferroptosis readout; single lab\",\n      \"pmids\": [\"40652527\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DMM (dimethyl malonate) disrupts the NCOA4-FTH1 protein-protein interaction in brain cortex (shown by Co-IP), suppresses NCOA4 and LC3II while upregulating FTH1 and p62, inhibits ferritinophagy and lysosomal Fe2+ accumulation, and protects against ferroptosis in neonatal HIBD; the anti-ferroptotic effects of DMM require FTH1 (reversed by Fth1 knockdown).\",\n      \"method\": \"Co-immunoprecipitation, Western blot, immunofluorescence (FTH1-LAMP2 colocalization), Fth1 knockdown rescue, neonatal MCAO mouse model\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — Co-IP confirms NCOA4-FTH1 interaction disruption; organelle-level imaging; FTH1-dependent rescue confirmed; in vivo validation\",\n      \"pmids\": [\"40749519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Neurofilament light chain (NF-L) treatment of microglia triggers secretion of FTH1-containing exosomes; these exosomes induce neuronal membrane lipid peroxidation and neuronal loss; blocking Fth1 expression attenuates this oxidative damage, showing that secreted/exosomal FTH1 can promote ferroptosis-like oxidative damage in a non-cell-autonomous manner.\",\n      \"method\": \"Microglia-neuron co-culture/conditioned medium, exosome isolation, CKK8 cell death assay, C11-Bodipy lipid peroxidation assay, Fth1 siRNA knockdown\",\n      \"journal\": \"Oxidative medicine and cellular longevity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — exosome isolation and Fth1 knockdown rescue provide orthogonal evidence; single lab\",\n      \"pmids\": [\"35368870\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FTH1 encodes the ferroxidase heavy chain subunit of the ferritin heteropolymer; it oxidizes redox-active Fe2+ to Fe3+ for storage, thereby suppressing labile iron-dependent lipid peroxidation and ferroptosis. Its degradation is controlled by ferritinophagy through direct binding to the cargo receptor NCOA4, with NCOA4 ubiquitination regulated by deubiquitinases such as OTULIN, and FTH1 protein stability controlled by E3 ubiquitin ligases (SMURF1) and chaperones (CRYAB via lactylation-dependent proteasomal protection). FTH1 mRNA is post-transcriptionally regulated by multiple RNA-binding proteins (RSL1D1 via 3'-UTR binding, NSUN5/TRAP1 via m5C methylation) and epitranscriptomic writers/erasers (METTL14/METTL1-mediated m6A/m7G reducing stability; FTO/Alkbh5-mediated demethylation stabilizing it via YTHDF1), and transcriptionally regulated by MAZ, NUPR1, TFEB, MBD5/KAT2A, and epigenetically by PRMT5/DNMT3B. FTH1 also localizes to the nucleus where it interacts with BRD2 to suppress ferroptosis-related gene expression. Loss of FTH1 increases ROS, activates HIF-1α/CXCR4/NF-κB signaling promoting EMT-like phenotypes in leukemia cells, and suppresses c-MYC in breast cancer. In neurons, FTH1 can be secreted in exosomes to propagate oxidative damage. Disease-causing C-terminal truncations of FTH1 escape nonsense-mediated decay, elevate ferritin protein, and impair iron-storage capacity via disruption of the 4-fold pores, acting through a dominant toxic gain-of-function mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"FTH1 encodes the ferroxidase heavy-chain subunit of ferritin, which assembles into higher-order 24-mer cages that sequester redox-active iron and thereby restrain ROS production and ferroptotic cell death [#4, #10, #11]. By oxidizing and storing labile Fe2+, FTH1 functions as a central brake on the ferritinophagy–ferroptosis cycle: its turnover is governed by autophagic degradation through direct binding to the cargo receptor NCOA4, and disrupting the NCOA4–FTH1 interaction blocks ferritinophagy and the release of bioavailable iron [#7, #9, #35]. FTH1 protein stability is further set by competing post-translational machinery—the E3 ligase SMURF1 drives its ubiquitination and degradation, while the chaperone CRYAB protects it from proteasomal turnover in a lactylation-dependent manner [#27, #24]; upstream, deubiquitination of NCOA4 by OTULIN and recruitment by LCN2 tune the rate of ferritinophagic FTH1 loss [#31, #26]. FTH1 abundance is set transcriptionally by activators including MAZ, NUPR1, and MBD5/KAT2A and repressed by TFEB and by estrogen-driven PRMT5/DNMT3B promoter methylation [#15, #25, #3, #20, #6], and post-transcriptionally through 3'-UTR binding by RSL1D1 and a dense epitranscriptomic layer in which m6A (METTL14/FTO) and m7G (METTL1) marks, read by YTHDF1, control FTH1 mRNA stability and translation [#18, #23, #29, #19]. Through these controls FTH1 sets ferroptosis sensitivity across many cell types, acting as a tumor suppressor upstream of c-MYC in breast cancer and restraining a ROS/HIF-1α/CXCR4/NF-κB invasion axis in leukemia [#12, #8]. Heterozygous C-terminal nonsense variants (e.g. p.Phe171*) escape nonsense-mediated decay, elevate ferritin protein, disrupt the 4-fold pores, and cause disease through a dominant toxic gain-of-function mechanism [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that an FTH1-derived placental variant (PLIF) carries immunomodulatory activity distinct from canonical iron storage, hinting at functions beyond ferritin assembly.\",\n      \"evidence\": \"cDNA cloning, immunolocalization, and in vitro lymphocyte proliferation assays from placenta\",\n      \"pmids\": [\"11821435\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PLIF is a C-terminally substituted variant, not full-length FTH1\", \"mechanism of lymphocyte suppression not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Dissected the signaling route by which the FTH1-derived C48 domain elicits IL-10, defining a calcium/calmodulin-p38 MAPK pathway.\",\n      \"evidence\": \"Cytokine ELISA with calmodulin and p38 inhibitors in monocytes\",\n      \"pmids\": [\"12670872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"pertains to the PLIF variant rather than canonical FTH1\", \"receptor for C48 unidentified\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed FTH1 has a direct protein-interaction role in apoptosis control by binding Daxx and suppressing Fas-Daxx-ASK1-JNK1 signaling, beyond its iron-storage function.\",\n      \"evidence\": \"Yeast two-hybrid, GST pull-down, Co-IP, and JNK pathway assays\",\n      \"pmids\": [\"21573799\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"interaction interface not mapped\", \"physiological relevance in vivo untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined transcriptional control of Fth1 in vivo, showing MBD5 enhances Fth1 transcription via KAT2A-dependent histone acetylation to prevent iron overload.\",\n      \"evidence\": \"Conditional knockout mice, luciferase promoter assay, histone acetylation analysis\",\n      \"pmids\": [\"24750026\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"direct MBD5 promoter occupancy not shown\", \"tissue specificity beyond intestine unaddressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Confirmed that human FTH1 self-assembles into 24-mer cages and confers cytoprotection against pro-death and metal stress, validating its core antioxidant/storage role.\",\n      \"evidence\": \"Heterologous expression in yeast, EM, viability assays\",\n      \"pmids\": [\"26886577\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"non-mammalian system\", \"ferroxidase kinetics not measured\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed FTH1 as a central node of the ferritinophagy-ferroptosis cycle, where its overexpression impairs NCOA4-dependent ferritin degradation and suppresses ferroptosis.\",\n      \"evidence\": \"siRNA/overexpression, autophagy inhibitors, mitochondrial assays in PC-12 cells\",\n      \"pmids\": [\"32959272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct FTH1-NCOA4 binding not assayed in this study\", \"single neuronal cell line\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Linked FTH1 loss to a pro-invasive program, showing FTH knockdown raises ROS and drives a HIF-1α/CXCR4/NF-κB EMT-like axis in leukemia.\",\n      \"evidence\": \"Stable shRNA, motility assays, pharmacological rescue (NAC/AMD3100/IκB inhibitor)\",\n      \"pmids\": [\"32432042\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"axis correlative downstream of ROS\", \"single cell line\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated epigenetic silencing of FTH1 by estrogen via PRMT5-dependent DNA methylation, connecting hormonal signaling to ferritin levels in liver cancer.\",\n      \"evidence\": \"ChIP, siRNA knockdown, methylation and demethylation rescue\",\n      \"pmids\": [\"32476555\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct DNMT3B-PRMT5 cooperation mechanism not resolved\", \"single tumor type\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Pinpointed NCOA4 as the druggable interaction target upstream of FTH1, with a small molecule directly disrupting NCOA4-FTH1 binding to block ferritinophagy and ferroptosis.\",\n      \"evidence\": \"Recombinant protein binding, PPI disruption, ferroptosis and stroke models\",\n      \"pmids\": [\"34235259\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"binding interface residues not mapped\", \"selectivity of the compound beyond NCOA4 untested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed FTH1 ferroxidase function determines ferroptosis sensitivity across tumor contexts, with overexpression reducing ROS and inducing GPX4 while abrogating ferroptosis-based therapy.\",\n      \"evidence\": \"Overexpression, ROS/lipid peroxide measurement, Seahorse, GPX4 blots, xenografts\",\n      \"pmids\": [\"34965856\", \"34445601\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanistic link between FTH1 and GPX4 induction unresolved\", \"correlative in single labs\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established FTH1 as a tumor suppressor upstream of c-MYC in breast cancer through epistasis between FTH1 and c-MYC manipulation.\",\n      \"evidence\": \"siRNA/overexpression, proliferation, mammosphere, c-MYC blots\",\n      \"pmids\": [\"34551213\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism linking FTH1 to c-MYC not defined\", \"single cancer type\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed a ceRNA layer controlling FTH1, where FTH1 pseudogenes sponge oncogenic miRNAs to protect FTH1 mRNA and regulate intracellular iron.\",\n      \"evidence\": \"miRNA screen, luciferase reporters, growth assays, xenografts\",\n      \"pmids\": [\"29240947\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"relative contribution of individual pseudogenes unclear\", \"single cancer type\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered an m5C methylation mechanism for FTH1/FTL mRNA, with NSUN5 (aided by TRAP1) marking the transcripts to sustain FTH1 protein and restrain ferroptosis.\",\n      \"evidence\": \"RIP, Co-IP, m5C assays, overexpression/knockdown in BMSCs\",\n      \"pmids\": [\"35249107\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"m5C reader for FTH1 not identified\", \"single cell system\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified MAZ as a direct transcriptional activator of FTH1 within a lncRNA TUG1/MAZ/FTH1 axis modulating ferroptosis in glioma.\",\n      \"evidence\": \"ChIP, luciferase, overexpression/knockdown, in vivo ferroptosis assays\",\n      \"pmids\": [\"36164395\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"other MAZ target contributions not excluded\", \"single tumor type\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned SIRT6 as a common upstream node coordinating both NCOA4/FTH1 ferritinophagy and Nrf2/GPX4 arms of ferroptosis defense.\",\n      \"evidence\": \"SIRT6 knockdown/overexpression in cells and rats, ferroptosis markers\",\n      \"pmids\": [\"36463827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct SIRT6 targets in these arms not defined\", \"correlative pathway placement\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Extended FTH1 biology to non-cell-autonomous damage, showing microglia secrete FTH1-containing exosomes that promote neuronal lipid peroxidation.\",\n      \"evidence\": \"Conditioned medium/exosome isolation, lipid peroxidation assays, Fth1 knockdown\",\n      \"pmids\": [\"35368870\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism of FTH1 loading into exosomes unknown\", \"redox role of secreted FTH1 not biochemically defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a Mendelian disease mechanism: C-terminal FTH1 nonsense variants escape NMD, disrupt the 4-fold pores, and cause a dominant toxic gain-of-function with elevated ferritin and oxidative stress.\",\n      \"evidence\": \"Exome sequencing, patient fibroblast assays, ASO knockdown rescue across five patients\",\n      \"pmids\": [\"37660254\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"organ-level pathophysiology in patients not fully characterized\", \"structural pore disruption inferred, not solved structurally\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified RSL1D1 as a 3'-UTR-binding stabilizer of FTH1 mRNA linking FTH1 abundance to ferroptosis and senescence.\",\n      \"evidence\": \"RIP, siRNA knockdown, Fe2+/MDA/GPX4 readouts in colorectal cancer\",\n      \"pmids\": [\"36913375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"RSL1D1 binding motif on FTH1 UTR not mapped\", \"single cancer type\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolved m7G control of FTH1, where METTL1 raises FTH1 mRNA but suppresses its translation and matures a miR-26a that further represses FTH1 to promote ferroptosis.\",\n      \"evidence\": \"AlkAniline-Seq, blots, miRNA manipulation, xenograft\",\n      \"pmids\": [\"38040806\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism of translation suppression by m7G not fully defined\", \"single tumor type\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established TFEB as a direct transcriptional repressor of FTH1 that drives ferritinophagy downstream of PTPRC loss.\",\n      \"evidence\": \"Luciferase, ChIP, siRNA knockdown in osteosarcoma\",\n      \"pmids\": [\"37851191\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TFEB direct vs autophagy-program-mediated effect not fully separated\", \"single tumor type\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed autophagic FTH1 degradation underlies a therapeutic vulnerability, with AKT1 loss raising autophagy flux to deplete FTH1 and sensitize resistant ovarian cancer to ferroptosis.\",\n      \"evidence\": \"AKT1 knockdown, autophagy flux and FTH1 protein assays\",\n      \"pmids\": [\"37011414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NCOA4-dependence not directly tested here\", \"single resistance model\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected myeloid FTH1 to inflammatory signaling, placing it upstream of a DMT1-iron-STAT3 axis in colitis.\",\n      \"evidence\": \"Myeloid-specific FTH1 cKO, DSS colitis, STAT3 pharmacology\",\n      \"pmids\": [\"36745026\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanistic link from FTH1 to DMT1 unresolved\", \"ferroptosis contribution not isolated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined opposing epitranscriptomic regulators of FTH1: METTL14-deposited m6A destabilizes FTH1 mRNA, while FTO erases m6A and YTHDF1/2 read it to control FTH1 expression and ferroptosis.\",\n      \"evidence\": \"Luciferase/qRT-PCR (METTL14) and MeRIP/RIP (FTO, YTHDF1/2) with functional assays\",\n      \"pmids\": [\"38738555\", \"39848345\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"context-dependence of reader outcome (stability vs translation) not reconciled\", \"single tissue per study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined post-translational protein-stability control of FTH1 by competing machinery: CRYAB protects FTH1 from proteasomal degradation via lactylation, while SMURF1 ubiquitinates FTH1 for degradation, governing ferroptosis and differentiation.\",\n      \"evidence\": \"IP-MS/Co-IP, proteasome inhibitors (CRYAB); Co-IP ubiquitination and muscle cKO (SMURF1)\",\n      \"pmids\": [\"38787373\", \"39941157\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ubiquitination sites on FTH1 not mapped\", \"interplay between CRYAB and SMURF1 not tested together\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified NUPR1 as a direct transcriptional activator of FTH1 conferring ferroptosis resistance via a circPIAS1/miR-455-3p/NUPR1 axis in HCC.\",\n      \"evidence\": \"RIP, luciferase, RNA pulldown, FISH, ChIP, xenograft\",\n      \"pmids\": [\"38802795\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NUPR1 promoter binding site on FTH1 not detailed\", \"single cancer type\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended upstream control of ferritinophagy to LCN2, which interacts with NCOA4 under high phosphate to accelerate FTH1 degradation and ferroptosis in vascular calcification.\",\n      \"evidence\": \"Co-IP, LCN2 KO/OE mice, ferroptosis/calcification markers\",\n      \"pmids\": [\"39613734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LCN2 effect on NCOA4-FTH1 binding is indirect/inferred\", \"phosphate-dependence mechanism unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed FTH1 protects cartilage by limiting ferroptosis and suppressing MAPK signaling in osteoarthritis.\",\n      \"evidence\": \"Chondrocyte knockdown, adenoviral overexpression in DMM model, MAPK blots\",\n      \"pmids\": [\"38609896\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanistic link from FTH1 to MAPK unresolved\", \"single disease model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Validated FTH1 as a direct druggable protein target, with CT-1 binding FTH1 to trigger NCOA4-mediated ferritinophagy and ferroptosis in tumors.\",\n      \"evidence\": \"Target identification, overexpression rescue, in vivo tumor model\",\n      \"pmids\": [\"39809268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"binding site on FTH1 not mapped\", \"selectivity not fully profiled\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated OTULIN deubiquitination of NCOA4 as a control point that indirectly sets FTH1 levels and hepatocyte ferroptosis.\",\n      \"evidence\": \"OTULIN stable lines, ubiquitination assays, APAP mouse model\",\n      \"pmids\": [\"40158433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct OTULIN-NCOA4 enzymology not fully characterized\", \"single injury model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected mechanical tension to iron handling via FTH1 phase separation, showing low tension raises FTH1 and suppresses NCOA4-driven ferritinophagy and ferroptosis.\",\n      \"evidence\": \"Tension manipulation, NCOA4 knockdown, phase separation imaging\",\n      \"pmids\": [\"39988734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"molecular sensor coupling tension to NCOA4 unidentified\", \"physiological generality unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Added a further epitranscriptomic relay, the Alkbh5-Ythdf1-Fth1 axis, promoting FTH1 translation to inhibit cardiomyocyte ferroptosis.\",\n      \"evidence\": \"MeRIP, RIP, reciprocal knockdown, H/R and MIRI rat models\",\n      \"pmids\": [\"40251485\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct vs Ythdf1-mediated FTH1 regulation by Alkbh5 not separated\", \"single disease context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a nuclear function for FTH1, where it associates with BRD2 to support its stability and suppress ferroptosis-related gene expression in aggressive NSCLC.\",\n      \"evidence\": \"Co-IP across NSCLC cell lines, siRNA silencing, ferroptosis markers\",\n      \"pmids\": [\"40652527\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"nuclear import mechanism of FTH1 unknown\", \"interaction specificity to BRD2 vs BRD4 mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided strong validation of NCOA4-FTH1 disruption as a neuroprotective strategy, showing DMM blocks the interaction, inhibits ferritinophagy, and protects in an FTH1-dependent manner.\",\n      \"evidence\": \"Co-IP, FTH1-LAMP2 imaging, Fth1 knockdown rescue, neonatal MCAO model\",\n      \"pmids\": [\"40749519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DMM target specificity beyond the NCOA4-FTH1 interaction not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the dense, partly redundant regulatory layers (transcriptional, epitranscriptomic, ubiquitin/chaperone, and ferritinophagic) are integrated in a single cell to set FTH1 levels, and how nuclear/secreted FTH1 pools relate mechanistically to the cytosolic iron-storage cage, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no unified model reconciling competing regulators in one system\", \"ferroxidase enzymology of human FTH1 not directly measured in the corpus\", \"structural basis of nuclear FTH1-BRD2 and exosomal FTH1 unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016491\", \"supporting_discovery_ids\": [10, 11, 4]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [10, 11, 9]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 32]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [34]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [36]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 9, 35, 27]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7, 21, 31, 32]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 10, 11]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [18, 23, 29, 19]}\n    ],\n    \"complexes\": [\"ferritin (heteropolymer with FTL)\"],\n    \"partners\": [\"NCOA4\", \"BRD2\", \"CRYAB\", \"SMURF1\", \"Daxx\", \"RSL1D1\", \"NSUN5\", \"YTHDF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":6,"faith_pct":83.33333333333333}}