RARE DISEASE
FTH1-related iron overload
FTH1-related iron overload
FTH1-related iron overload
Synonyms: FTH1-associated iron overload
Synonyms: FTH1-associated iron overload
Synonyms: FTH1-associated iron overload
Drug discovery
2
drugs
With orphan designations
Overview
FTH1-related iron overload is a rare autosomal dominant disorder caused by heterozygous nonsense variants in the FTH1 gene, impairing ferritin heavy-chain function. This leads to systemic iron accumulation in the liver, heart, bone marrow, and brain, with elevated serum ferritin and transferrin saturation [1][2][6]. Pediatric patients often present with progressive neurodegeneration (e.g., developmental delay, epilepsy) and neuroimaging features of brain iron deposition, overlapping with neurodegeneration with brain iron accumulation (NBIA) disorders [1][6].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism
Research Papers
29 drug discovery papers about FTH1-related iron overload, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
29 drug discovery papers about FTH1-related iron overload, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-03-01 | MITF programs macrophage iron homeostasis to drive gut-liver inflammatory axis in early life
Systemic chronic inflammation (SCI) is a key driver of non-communicable diseases. Early-life stressors disrupt intestinal homeostasis, promoting SCI, but the mechanisms are unclear. Using translational models, we identify dysregulated iron homeostasis as a pivotal disruptor of intestinal barrier integrity. Single-cell profiling reveals that neutrophils and macrophages mediate iron-dependent mucosal defense. Stress induces iron overload in gut epithelial cells and macrophages, a process governed by the transcription factor MITF. MITF-mediated iron dysregulation in macrophages is associated with neutrophil recruitment to the lamina propria, concomitant with elevated levels of the CXCL8, synchronizing with hepatic inflammatory and metabolic dysregulation via the gut-liver axis. Mechanistically, abnormal iron homeostasis couples with interferon signaling, and MITF modulates iron-related genes (FTH1, TFRC, and FRRS1). Therapeutic mitigation of iron dyshomeostasis preserves barrier function and attenuates systemic inflammation. Our findings identify MITF as a key regulator of gut-liver inflammatory cascades and nominate abnormal iron homeostasis as a target for early-life inflammatory disorders.
2026-02-16 | Ferritinophagy and organ injury
Ferritinophagy is a selective form of macroautophagy/autophagy that mediates the degradation of ferritin complexes, releasing stored iron, and maintaining intracellular iron homeostasis. Proper regulation of ferritinophagy is essential for cellular adaptation to metabolic stress, whereas dysregulation disrupts iron balance and contributes to pathological processes. Excessive ferritinophagy leads to iron overload and reactive oxygen species accumulation, driving oxidative stress, ferroptosis, and inflammation, which are key contributors to cellular injury and progressive organ dysfunction. Despite advances in our understanding of autophagy and ferroptosis, the specific role of ferritinophagy in organ-specific injury remains unclear. In this review, we provide a comprehensive overview of the molecular mechanisms of ferritinophagy and critically examine its emerging roles in the pathogenesis of injuries to the heart, liver, lungs, and kidneys. We further highlight the therapeutic potential of targeting ferritinophagy and propose future research directions aimed at harnessing this pathway for the treatment of organ injuries.Abbreviations: 3-MA: 3-methyladenine; ACO1/IRP1: aconitase 1; AKI: acute kidney injury; ARDS: acute respiratory distress syndrome; ATG: autophagy related; BECN1: beclin 1; CARM1/PRMT4: coactivator associated arginine methyltransferase 1; CIRBP: cold inducible RNA binding protein; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; ELAVL1: ELAV like RNA binding protein 1; Fer-1: ferrostatin-1; FTH1: ferritin heavy chain 1; GABARAP: GABA type A receptor-associated protein; GPX4: glutathione peroxidase 4; HAMP/hepcidin: hepcidin antimicrobial peptide; HCC: hepatocellular carcinoma; HERC2: HECT and RLD domain containing E3 ubiquitin protein ligase 2; HSCs: hepatic stellate cells; IL13: interleukin 13; IL6: interleukin 6; I/R: ischemia-reperfusion; IRE: iron-responsive element; IREB2/IRP2: iron responsive element binding protein 2; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MDA: malondialdehyde; MIOX: myo-inositol oxygenase; NCOA4: nuclear receptor coactivator 4; NFE2L2/Nrf2: NFE2 like bZIP transcription factor 2; ROS: reactive oxygen species; SIRT1: sirtuin 1; SLC40A1/ferroportin: solute carrier family 40 member 1; STAT3: signal transducer and activator of transcription 3; STEAP3: STEAP3 metalloreductase; TFRC/TfR1: transferrin receptor; USP11: ubiquitin specific peptidase 11; YAP1: Yes1 associated transcriptional regulator.
2024-11-05 | Hetrombopag, an Emerging Iron-Chelating Agent, Alleviates Systemic Iron Overload
Background: Iron overload is a syndrome in which excessive iron accumulates in the body, leading to tissue damage and functional disorders. This condition is common in patients with refractory anaemia who receive long-term red blood cell transfusions. Hetrombopag (HPAG) is a new generation, oral, small molecule, nonpeptide thrombopoietin receptor agonist that can chelate iron and alleviate iron overload while promoting haematopoiesis. Nevertheless, there is currently a lack of research on the iron-chelating function of HPAG, and its mechanism of regulating iron metabolism in the body is not clear. Aims: The aim of this study was to clarify the iron-chelating function of HPAG, its effects on haematopoiesis, immune abnormalities, and tissue damage caused by iron overload and explore its potential mechanism of systemic iron metabolism, providing a new theoretical basis for the treatment of haematological diseases with HPAG. Methods: Iron overload was induced in mice by intraperitoneal injection of iron dextran, and treatment was performed with HPAG, deferasirox (DFX, an iron chelator), or ferrostatin-1 (Fer-1, a ferroptosis inhibitor). The iron-chelating function of HPAG and its effects on haematopoiesis, immune abnormalities, and tissue damage caused by iron overload were clarified in vivo, and the underlying mechanism was explored via transcriptomics and lipidomics. Results: Iron-overloaded mice treated with HPAG or DFX showed recovery in terms the of weight loss, hepatomegaly, histopathological iron deposition, reduced glutathione/oxidized glutathione (GSH/GSSG) balance and superoxide dismutase (SOD) activity, and increased non-transferrin-bound iron (NTBI) and malondialdehyde (MDA) levels caused by iron overload. Importantly, compared with untreated mice, iron-overloaded mice treated with HPAG, DFX, or Fer-1 presented restored tissue fibrosis and increased numbers of long-term haematopoietic stem cells (LT-HSCs), short-term haematopoietic stem cells (ST-HSCs), and Treg cells and an increased CD4/CD8 ratio. Lipidomic and transcriptomic data from the liver and c-kit+ cells in bone marrow revealed that HPAG induces molecular changes consistent with intracellular iron reduction and lipid peroxidation inhibition, with decreased expression of the HAMP, FTH1, BMP6, and HMOX1 genes. Furthermore, compared with those in DFX-treated mice, immune response-related signalling pathways, especially those related to the inhibition of the response to type I interferon, were significantly enriched in HPAG-treated mice. Conclusion: HPAG is an emerging iron-chelating agent and a potential inhibitor of ferroptosis that alleviates tissue damage, haematopoietic stem cell injury, and immune abnormalities caused by systemic iron overload and provides an immunoregulatory function.
2023-11-15 | High concentration of iron ions contributes to ferroptosis-mediated testis injury
Abstract In order to explore the effect of different concentrations of iron ions on ferroptosis in mouse testes, Kunming mice were randomly divided into control group (normal saline), low iron concentration group (25mg/kg), high iron concentration group (70mg/kg) and deferoxamine group (40mg/kg). The mice were injected continuously for 7 days and their body weight was measured. At the end of the experiment, the organ weight, sperm count, and malformation rate were measured. Testicular tissue, the pathological and ultrastructural changes in spermatogenic tubules were also observed by using hematoxylin eosin (HE) staining and transmission electron microscopy. The changes in transcription levels of related genes and serum biochemical indicators were measured in mouse testicular tissues. The results showed that higher iron concentration may inhibit the growth of mice, reduce the organ coefficients of testis, heart, and liver, and increase the rate of sperm malformation and mortality. Supplementation of iron ion in high concentration can negatively affect the male reproductive system by reducing the sperm count and causing malformation and structural damage in seminiferous tubules and sperm cells. In addition, the iron concentration also affected the immune response and blood coagulation ability by influencing the red blood cells, white blood cells and platelets. The results showed that iron ions may affect mice testicular tissue and induce ferroptosis by altering the expression of ferroptosis related genes. Though, the degree of effect was different for the different concentrations of iron ions. The study also revealed the potential role of deferoxamine to inhibit the occurrence of ferroptosis. Though, the damages caused to the testis by deferoxamine supplementation suggests the need for further researches in this direction.
2023-03-06 | Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis
Abstract A lack of the mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 ( Mto1 ) was recently shown to induce proteostress in embryonic stem cells. Since erythroid precursors actively synthesize the hemoglobin protein, we hypothesized that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal due to niche-independent defective terminal erythroid differentiation. Mechanistically, mitochondrial oxidative phosphorylation complex-I was severely defective in the Mto1 cKO fetal liver and this was followed by cytoplasmic iron accumulation. Overloaded cytoplasmic iron promoted heme biosynthesis and enhanced the expression of embryonic hemoglobin proteins, which induced an unfolded protein response via the IRE1α-Xbp1 signaling pathway in Mto1 cKO erythroblasts. An iron chelator rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro . The new point of view provided by this novel non-energy-related molecular mechanism may lead to a breakthrough in mitochondrial research.
proteins
2022-09-06 | A crosstalk between hepcidin and IRE/IRP pathways controls ferroportin expression and determines serum iron levels in mice
The iron hormone hepcidin is transcriptionally activated by iron or inflammation via distinct, partially overlapping pathways. We addressed how iron affects inflammatory hepcidin levels and the ensuing hypoferremic response. Dietary iron overload did not mitigate hepcidin induction in lipopolysaccharide (LPS)-treated wild type mice but prevented effective inflammatory hypoferremia. Likewise, LPS modestly decreased serum iron in hepcidin-deficient Hjv -/- mice, model of hemochromatosis. Synthetic hepcidin triggered hypoferremia in control but not iron-loaded wild type animals. Furthermore, it dramatically decreased hepatic and splenic ferroportin in Hjv -/- mice on standard or iron-deficient diet, but only triggered hypoferremia in the latter. Mechanistically, iron antagonized hepcidin responsiveness by inactivating IRPs in the liver and spleen to stimulate f erroportin mRNA translation. Prolonged LPS treatment eliminated ferroportin mRNA and permitted hepcidin-mediated hypoferremia in iron-loaded mice. Thus, de novo ferroportin synthesis is a critical determinant of serum iron and finetunes hepcidin-dependent functional outcomes. Our data uncover a crosstalk between hepcidin and IRE/IRP systems that controls tissue ferroportin expression and determines serum iron levels. Moreover, they suggest that hepcidin supplementation therapy is more efficient when combined with iron depletion.
small molecules
2026-03-01 | MITF programs macrophage iron homeostasis to drive gut-liver inflammatory axis in early life
Systemic chronic inflammation (SCI) is a key driver of non-communicable diseases. Early-life stressors disrupt intestinal homeostasis, promoting SCI, but the mechanisms are unclear. Using translational models, we identify dysregulated iron homeostasis as a pivotal disruptor of intestinal barrier integrity. Single-cell profiling reveals that neutrophils and macrophages mediate iron-dependent mucosal defense. Stress induces iron overload in gut epithelial cells and macrophages, a process governed by the transcription factor MITF. MITF-mediated iron dysregulation in macrophages is associated with neutrophil recruitment to the lamina propria, concomitant with elevated levels of the CXCL8, synchronizing with hepatic inflammatory and metabolic dysregulation via the gut-liver axis. Mechanistically, abnormal iron homeostasis couples with interferon signaling, and MITF modulates iron-related genes (FTH1, TFRC, and FRRS1). Therapeutic mitigation of iron dyshomeostasis preserves barrier function and attenuates systemic inflammation. Our findings identify MITF as a key regulator of gut-liver inflammatory cascades and nominate abnormal iron homeostasis as a target for early-life inflammatory disorders.
2026-02-16 | Ferritinophagy and organ injury
Ferritinophagy is a selective form of macroautophagy/autophagy that mediates the degradation of ferritin complexes, releasing stored iron, and maintaining intracellular iron homeostasis. Proper regulation of ferritinophagy is essential for cellular adaptation to metabolic stress, whereas dysregulation disrupts iron balance and contributes to pathological processes. Excessive ferritinophagy leads to iron overload and reactive oxygen species accumulation, driving oxidative stress, ferroptosis, and inflammation, which are key contributors to cellular injury and progressive organ dysfunction. Despite advances in our understanding of autophagy and ferroptosis, the specific role of ferritinophagy in organ-specific injury remains unclear. In this review, we provide a comprehensive overview of the molecular mechanisms of ferritinophagy and critically examine its emerging roles in the pathogenesis of injuries to the heart, liver, lungs, and kidneys. We further highlight the therapeutic potential of targeting ferritinophagy and propose future research directions aimed at harnessing this pathway for the treatment of organ injuries.Abbreviations: 3-MA: 3-methyladenine; ACO1/IRP1: aconitase 1; AKI: acute kidney injury; ARDS: acute respiratory distress syndrome; ATG: autophagy related; BECN1: beclin 1; CARM1/PRMT4: coactivator associated arginine methyltransferase 1; CIRBP: cold inducible RNA binding protein; CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; ELAVL1: ELAV like RNA binding protein 1; Fer-1: ferrostatin-1; FTH1: ferritin heavy chain 1; GABARAP: GABA type A receptor-associated protein; GPX4: glutathione peroxidase 4; HAMP/hepcidin: hepcidin antimicrobial peptide; HCC: hepatocellular carcinoma; HERC2: HECT and RLD domain containing E3 ubiquitin protein ligase 2; HSCs: hepatic stellate cells; IL13: interleukin 13; IL6: interleukin 6; I/R: ischemia-reperfusion; IRE: iron-responsive element; IREB2/IRP2: iron responsive element binding protein 2; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MDA: malondialdehyde; MIOX: myo-inositol oxygenase; NCOA4: nuclear receptor coactivator 4; NFE2L2/Nrf2: NFE2 like bZIP transcription factor 2; ROS: reactive oxygen species; SIRT1: sirtuin 1; SLC40A1/ferroportin: solute carrier family 40 member 1; STAT3: signal transducer and activator of transcription 3; STEAP3: STEAP3 metalloreductase; TFRC/TfR1: transferrin receptor; USP11: ubiquitin specific peptidase 11; YAP1: Yes1 associated transcriptional regulator.
2024-11-05 | Hetrombopag, an Emerging Iron-Chelating Agent, Alleviates Systemic Iron Overload
Background: Iron overload is a syndrome in which excessive iron accumulates in the body, leading to tissue damage and functional disorders. This condition is common in patients with refractory anaemia who receive long-term red blood cell transfusions. Hetrombopag (HPAG) is a new generation, oral, small molecule, nonpeptide thrombopoietin receptor agonist that can chelate iron and alleviate iron overload while promoting haematopoiesis. Nevertheless, there is currently a lack of research on the iron-chelating function of HPAG, and its mechanism of regulating iron metabolism in the body is not clear. Aims: The aim of this study was to clarify the iron-chelating function of HPAG, its effects on haematopoiesis, immune abnormalities, and tissue damage caused by iron overload and explore its potential mechanism of systemic iron metabolism, providing a new theoretical basis for the treatment of haematological diseases with HPAG. Methods: Iron overload was induced in mice by intraperitoneal injection of iron dextran, and treatment was performed with HPAG, deferasirox (DFX, an iron chelator), or ferrostatin-1 (Fer-1, a ferroptosis inhibitor). The iron-chelating function of HPAG and its effects on haematopoiesis, immune abnormalities, and tissue damage caused by iron overload were clarified in vivo, and the underlying mechanism was explored via transcriptomics and lipidomics. Results: Iron-overloaded mice treated with HPAG or DFX showed recovery in terms the of weight loss, hepatomegaly, histopathological iron deposition, reduced glutathione/oxidized glutathione (GSH/GSSG) balance and superoxide dismutase (SOD) activity, and increased non-transferrin-bound iron (NTBI) and malondialdehyde (MDA) levels caused by iron overload. Importantly, compared with untreated mice, iron-overloaded mice treated with HPAG, DFX, or Fer-1 presented restored tissue fibrosis and increased numbers of long-term haematopoietic stem cells (LT-HSCs), short-term haematopoietic stem cells (ST-HSCs), and Treg cells and an increased CD4/CD8 ratio. Lipidomic and transcriptomic data from the liver and c-kit+ cells in bone marrow revealed that HPAG induces molecular changes consistent with intracellular iron reduction and lipid peroxidation inhibition, with decreased expression of the HAMP, FTH1, BMP6, and HMOX1 genes. Furthermore, compared with those in DFX-treated mice, immune response-related signalling pathways, especially those related to the inhibition of the response to type I interferon, were significantly enriched in HPAG-treated mice. Conclusion: HPAG is an emerging iron-chelating agent and a potential inhibitor of ferroptosis that alleviates tissue damage, haematopoietic stem cell injury, and immune abnormalities caused by systemic iron overload and provides an immunoregulatory function.
2023-11-15 | High concentration of iron ions contributes to ferroptosis-mediated testis injury
Abstract In order to explore the effect of different concentrations of iron ions on ferroptosis in mouse testes, Kunming mice were randomly divided into control group (normal saline), low iron concentration group (25mg/kg), high iron concentration group (70mg/kg) and deferoxamine group (40mg/kg). The mice were injected continuously for 7 days and their body weight was measured. At the end of the experiment, the organ weight, sperm count, and malformation rate were measured. Testicular tissue, the pathological and ultrastructural changes in spermatogenic tubules were also observed by using hematoxylin eosin (HE) staining and transmission electron microscopy. The changes in transcription levels of related genes and serum biochemical indicators were measured in mouse testicular tissues. The results showed that higher iron concentration may inhibit the growth of mice, reduce the organ coefficients of testis, heart, and liver, and increase the rate of sperm malformation and mortality. Supplementation of iron ion in high concentration can negatively affect the male reproductive system by reducing the sperm count and causing malformation and structural damage in seminiferous tubules and sperm cells. In addition, the iron concentration also affected the immune response and blood coagulation ability by influencing the red blood cells, white blood cells and platelets. The results showed that iron ions may affect mice testicular tissue and induce ferroptosis by altering the expression of ferroptosis related genes. Though, the degree of effect was different for the different concentrations of iron ions. The study also revealed the potential role of deferoxamine to inhibit the occurrence of ferroptosis. Though, the damages caused to the testis by deferoxamine supplementation suggests the need for further researches in this direction.
2023-03-06 | Mitochondrial translation regulates terminal erythroid differentiation by maintaining iron homeostasis
Abstract A lack of the mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 ( Mto1 ) was recently shown to induce proteostress in embryonic stem cells. Since erythroid precursors actively synthesize the hemoglobin protein, we hypothesized that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal due to niche-independent defective terminal erythroid differentiation. Mechanistically, mitochondrial oxidative phosphorylation complex-I was severely defective in the Mto1 cKO fetal liver and this was followed by cytoplasmic iron accumulation. Overloaded cytoplasmic iron promoted heme biosynthesis and enhanced the expression of embryonic hemoglobin proteins, which induced an unfolded protein response via the IRE1α-Xbp1 signaling pathway in Mto1 cKO erythroblasts. An iron chelator rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro . The new point of view provided by this novel non-energy-related molecular mechanism may lead to a breakthrough in mitochondrial research.
proteins
2022-09-06 | A crosstalk between hepcidin and IRE/IRP pathways controls ferroportin expression and determines serum iron levels in mice
The iron hormone hepcidin is transcriptionally activated by iron or inflammation via distinct, partially overlapping pathways. We addressed how iron affects inflammatory hepcidin levels and the ensuing hypoferremic response. Dietary iron overload did not mitigate hepcidin induction in lipopolysaccharide (LPS)-treated wild type mice but prevented effective inflammatory hypoferremia. Likewise, LPS modestly decreased serum iron in hepcidin-deficient Hjv -/- mice, model of hemochromatosis. Synthetic hepcidin triggered hypoferremia in control but not iron-loaded wild type animals. Furthermore, it dramatically decreased hepatic and splenic ferroportin in Hjv -/- mice on standard or iron-deficient diet, but only triggered hypoferremia in the latter. Mechanistically, iron antagonized hepcidin responsiveness by inactivating IRPs in the liver and spleen to stimulate f erroportin mRNA translation. Prolonged LPS treatment eliminated ferroportin mRNA and permitted hepcidin-mediated hypoferremia in iron-loaded mice. Thus, de novo ferroportin synthesis is a critical determinant of serum iron and finetunes hepcidin-dependent functional outcomes. Our data uncover a crosstalk between hepcidin and IRE/IRP systems that controls tissue ferroportin expression and determines serum iron levels. Moreover, they suggest that hepcidin supplementation therapy is more efficient when combined with iron depletion.
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Drug Discovery Landscape
2 orphan drug designations for FTH1-related iron overload.
2 orphan drug designations for FTH1-related iron overload.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Deferitrin | small molecules | EMA | [INACTIVE] Sanofi B.V. | |
Deferasirox [Exjade] | small molecules | EMA | Novartis Europharm Limited |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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