• Ferroptosis
• Iron
• MitoNEET
• Mitochondria
• Obesity

• Ferroptosis
• Humans
• Iron/metabolism
• Mitochondria/metabolism
• Oxidative Stress
• Animals
• Iron Overload/metabolism
• Reactive Oxygen Species/metabolism
• Homeostasis

• Animals
• Swine
• Dietary Supplements/analysis
• Iron/metabolism
• Iron/administration & dosage
• Iron/blood
• Female
• Animals, Newborn
• Pregnancy
• Anemia, Iron-Deficiency/veterinary
• Anemia, Iron-Deficiency/drug therapy
• Cesarean Section
• Premature Birth
• Administration, Oral
• Ferrous Compounds/administration & dosage
• Ferritins/blood
• Ferritins/metabolism
• Ferric Compounds/administration & dosage
• Diphosphates

• DILI
• Ferroptosis
• Gut-Liver Axis
• Liver Diseases
• Liver microenvironment
• NAFLD

• Ferroptosis/drug effects
• Humans
• Liver Diseases/pathology
• Liver Diseases/metabolism
• Liver Diseases/drug therapy
• Liver Diseases/therapy
• Animals
• Molecular Targeted Therapy

• 2023kykt07 Lu'an City Science and Technology Plan Project

• glucose metabolism
• iron overload
• magnetic resonance imaging
• pancreatic volume
• thalassemia

• na The E-MIOT project receives "no-profit support" from industrial sponsorships (Chiesi Farmaceu-tici S.p.A. and Bayer). The funders had no role in study design, data collection and analysis, de-cision to publish, or preparation of the manuscript.

• Mice
• Animals
• Hepcidins/genetics
• Hepcidins/metabolism
• Anemia/genetics
• Anemia/metabolism
• Iron/metabolism
• Liver/metabolism
• Bone Morphogenetic Protein 6/genetics
• Bone Morphogenetic Protein 6/metabolism
• Homeostasis

• R01 DK095112 NIDDK NIH HHS
• R01 DK107670 NIDDK NIH HHS
• R01 DK126680 NIDDK NIH HHS

• BMP/SMAD pathway
• Hemochromatosis
• Hepcidin
• Holo-transferrin
• Ubiquitin-proteasome degradation

• Male
• Rats
• Animals
• Prolyl Hydroxylases
• Prolyl-Hydroxylase Inhibitors/pharmacology
• Rats, Inbred Dahl
• Anemia/drug therapy
• Anemia/etiology
• Hypertension/genetics
• Renal Insufficiency, Chronic
• Procollagen-Proline Dioxygenase
• Sodium Chloride, Dietary
• Iron
• Cardiomegaly
• Fibrosis
• Hypoxia

• Animals
• Iron/metabolism
• Iron-Regulatory Proteins/genetics
• Iron-Regulatory Proteins/metabolism
• Transcription Factors/metabolism
• Homeostasis/physiology
• Oxidative Stress
• Mammals/metabolism

• GDF-11
• HSP70
• Microcytic anemia
• hepcidin
• ineffective erythropoiesis
• iron metabolism

• Humans
• Anemia, Hypochromic/genetics
• Anemia, Hypochromic/metabolism
• Genetic Therapy

• Erythroferrone
• Hepcidin
• Ineffective erythropoiesis
• Nontransferrin-bound iron

• apoptosis
• calcium overload
• cell death
• ferroptosis
• labile iron
• mitochondrial calcium uniporter
• oncosis

• biology
• catalysis
• electrons
• heart
• iron
• macrophages
• metabolism

• Animals
• Humans
• Cardiovascular Diseases/drug therapy
• Iron/metabolism
• Iron Overload/drug therapy
• Heart Failure/drug therapy
• Iron Deficiencies
• Mammals

• R01 HL140973 NHLBI NIH HHS
• R01 HL127646 NHLBI NIH HHS
• T32 HL069771 NHLBI NIH HHS
• F31 HL132552 NHLBI NIH HHS
• R01 HL140927 NHLBI NIH HHS
• R01 HL155953 NHLBI NIH HHS
• R01 HL138982 NHLBI NIH HHS

• Animals
• Mice
• beta-Thalassemia/genetics
• beta-Thalassemia/metabolism
• Erythropoietin/metabolism
• Hemochromatosis Protein/genetics
• Hemochromatosis Protein/metabolism
• Hepatocytes/metabolism
• Hepcidins/genetics
• Hepcidins/metabolism
• Homeostasis
• Iron/metabolism
• Iron Overload/genetics
• Iron Overload/metabolism
• Mice, Knockout
• Receptors, Transferrin/genetics
• Receptors, Transferrin/metabolism

• R01 DK087727 NIDDK NIH HHS
• R01 DK128068 NIDDK NIH HHS

• heart failure
• human model
• myocardial gathering proteins expression
• myocardial iron metabolism
• oxidative stress

• Cancer
• Chelators
• Chemotherapy
• Drug resistance
• Ferroptosis
• Iron

The liver is the major target organ of continued alcohol consumption at risk and resulting alcoholic liver disease (ALD) is the most common liver disease worldwide. The underlying molecular mechanisms are still poorly understood despite decades of scientific effort limiting our abilities to identify those individuals who are at risk to develop the disease, to develop appropriate screening strategies and, in addition, to develop targeted therapeutic approaches. ALD is predestined for the newly evolving translational medicine, as conventional clinical and health care structures seem to be constrained to fully appreciate this disease. This concept paper aims at summarizing the 15 years translational experience at the Center of Alcohol Research in Heidelberg, namely based on the long-term prospective and detailed characterization of heavy drinkers with mortality data. In addition, novel experimental findings will be presented. A special focus will be the long-known hepatic iron accumulation, the somewhat overlooked role of the hematopoietic system and novel insights into iron sensing and the role of hepcidin. Our preliminary work indicates that enhanced red blood cell (RBC) turnover is critical for survival in ALD patients. RBC turnover is not primarily due to vitamin deficiency but rather to ethanol toxicity directly targeted to erythrocytes but also to the bone marrow stem cell compartment. These novel insights also help to explain long-known aspects of ALD such as mean corpuscular volume of erythrocytes (MCV) and elevated aspartate transaminase (GOT/AST) levels. This work also aims at identifying future projects, naming unresolved observations, and presenting novel hypothetical concepts still requiring future validation.

• AOM/DSS mouse model
• cancer iron metabolism
• colitis-associated colorectal cancer
• inflammatory bowel disease
• iron deficiency
• iron overload

• anemia
• erythroferrone
• erythropoiesis
• erythropoietin
• hepcidin
• iron
• iron deficiency
• transferrin

• R01 DK095112 NIDDK NIH HHS
• UL1 TR002345 NCATS NIH HHS
• National Institute of Diabetes and Digestive and Kidney Diseases

Hemojuvelin (HJV) enhances signaling to the iron hormone hepcidin and its deficiency causes iron overload, a risk factor for hepatocellular carcinoma (HCC). We utilized Hjv^−/− mice to dissect mechanisms for hepatocarcinogenesis. We show that suboptimal treatment with diethylnitrosamine (DEN) triggers HCC only in Hjv^−/− but not wt mice. Liver proteomics data were obtained by mass spectrometry. Hierarchical clustering analysis revealed that Hjv deficiency and DEN elicit similar liver proteomic responses, including induction of mitochondrial proteins. Dietary iron overload of wt mice does not recapitulate the liver proteomic phenotype of Hjv^−/− animals, which is only partially corrected by iron depletion. Consistent with these data, primary Hjv^−/− hepatocytes exhibit mitochondrial hyperactivity, while aged Hjv^−/− mice develop spontaneous HCC. Moreover, low expression of HJV or hepcidin (HAMP) mRNAs predicts poor prognosis in HCC patients. We conclude that Hjv has a hepatoprotective function and its deficiency in mice promotes mitochondrial dysfunction and hepatocarcinogenesis.

Hemojuvelin (HJV), a BMP co-receptor promoting hepcidin expression in the liver, has a hepatoprotective function and its deficiency in mice triggers mitochondrial dysfunction and hepatocarcinogenesis.

• BMP
• anemia
• hemochromatosis
• hepcidin
• iron sensing
• liver

Liver sinusoidal endothelial cell–derived bone morphogenetic protein 6 (BMP6) and the BMP6–small mothers against decapentaplegic homolog (SMAD) signaling pathway are essential for the expression of hepcidin, the secretion of which is considered the systemic master switch of iron homeostasis. However, there are continued controversies related to the strong and direct suppressive effect of iron on hepatocellular hepcidin in vitro in contrast to in vivo conditions. Here, we directly studied the crosstalk between endothelial cells (ECs) and hepatocytes using in vitro coculture models that mimic hepcidin signaling in vivo. Huh7 cells were directly cocultured with ECs, and EC conditioned media (CM) were also used to culture Huh7 cells and primary mouse hepatocytes. To explore the reactions of ECs to surrounding iron, they were grown in the presence of ferric ammonium citrate and heme, two iron-containing molecules. We found that both direct coculture with ECs and EC-CM significantly increased hepcidin expression in Huh7 cells. The upstream SMAD pathway, including phosphorylated SMAD1/5/8, SMAD1, and inhibitor of DNA binding 1, was induced by EC-CM, promoting hepcidin expression. Efficient blockage of this EC-mediated hepcidin upregulation by an inhibitor of the BMP6 receptor ALK receptor tyrosine kinase 2/3 or BMP6 siRNA identified BMP6 as a major hepcidin regulator in this coculture system, which highly fits the model of hepcidin regulation by iron in vivo. In addition, EC-derived BMP6 and hepcidin were highly sensitive to levels of not only ferric iron but also heme as low as 500 nM. We here establish a hepatocyte–endothelial coculture system to fully recapitulate iron regulation by hepcidin using EC-derived BMP6.

• BMP6–SMAD pathway
• endothelial cells
• hepatocytes
• hepcidin
• iron metabolism

Liver-secreted hepcidin is the systemic master switch of iron homeostasis and decreased levels of hepcidin are considered to cause iron overload not only in hereditary hemochromatosis but also in hemolytic anemia and chronic liver diseases. The regulation of hepcidin is complex and its response to iron is still not completely understood.

To study the direct effect of iron on various established hepcidin signaling pathways in hepatoma cells or primary hepatocytes.

Hepcidin mRNA expression was studied by quantitative real-time (qRT)-PCR in the presence of various forms of iron including ferric ammonium citrate (FAC) in hepatoma cells (Huh7), murine primary hepatocytes and an established co-culture model of phorbol myristate acetate-differentiated THP-1 monocytes and Huh7 cells. To analyze hepcidin signaling, the response to bone morphogenetic protein 6 (BMP6), interleukin (IL)-6, IL-1β, hypoxia and lipopolysaccharide (LPS) were studied. Hepcidin and small mothers against decapentaplegic 6 (SMAD6) mRNA levels were assessed by qRT-PCR and the expression of phosphorylated signal transducer and activator of transcription 3 (phospho-STAT3), STAT3, phospho-SMAD1/5/8 and SMAD1 proteins were analyzed by western blot.

All iron III forms including FAC efficiently blocked hepcidin mRNA expression at non-toxic dosages in Huh7 cells or primary hepatocytes in a time and dose-dependent manner (P < 0.001; P < 0.05). Hepcidin blockage could be efficiently blunted by iron chelators salicylaldehyde isonicotinoyl hydrazone (SIH) and Desferal (P < 0.001). FAC also inhibited BMP6, hypoxia, IL-1β and IL-6-mediated hepcidin induction (P < 0.001; P < 0.001; P < 0.05; P < 0.001), and FAC also inhibited LPS-mediated hepatic hepcidin induction in co-culture model (P < 0.001). Moreover, FAC reduced SMAD6 mRNA and p-SMAD1/5/8 protein expression at basal or upon stimulation by BMP6 (P < 0.05; P < 0.01), and FAC also reduced SMAD6 and p-SMAD1/5/8 expression under hypoxia (P < 0.01; P < 0.05). However, FAC has no significant effect on p-STAT3 protein expression at basal or upon stimulation by various stimuli. Notably, in the presence of the BMP/SMAD signaling pathway inhibitor LDN193189 Hydrochloride (LDN), FAC was unable to further decrease hepcidin, SMAD6 and p-SMAD1/5/8 expression compared with LDN alone.

Iron directly blocks hepatocellular hepcidin signaling through the BMP/SMAD pathway but independent of STAT3. This mechanism may contribute to continued iron overload in many pathophysiological conditions ultimately causing a vicious cycle of continued hepcidin suppression.

• Hepcidin/iron metabolism
• Iron overload
• Inflammation
• Hypoxia
• BMP/SMAD
• STAT3

Hepcidin is a liver‐derived peptide hormone that limits iron egress from tissues to the bloodstream. It operates by binding to the iron exporter ferroportin, which blocks iron transport and tags ferroportin for degradation. Genetic hepcidin inactivation leads to hereditary hemochromatosis, a disease of iron overload. We used wild‐type and Hjv‐/‐ mice, a model of hemochromatosis, to examine the expression of ferroportin and other proteins of iron metabolism in hepcidin target tissues. The animals were previously subjected to dietary iron manipulations. In Hjv‐/‐ mice, hepcidin messenger RNA correlated significantly with hepatic iron load (r = 0.8211, P < 0.001), but was substantially lower compared with wild‐type controls. Duodenal ferroportin and divalent metal transporter 1 (DMT1), as well as splenic and hepatic ferroportin, were overexpressed in these animals. A high‐iron diet (2% carbonyl iron) suppressed duodenal DMT1 levels in both wild‐type and Hjv‐/‐ mice; however, it did not affect duodenal ferroportin expression in Hjv‐/‐ mice, and only reduced it in wild‐type mice. In contrast, the high‐iron diet decreased splenic ferroportin exclusively in Hjv‐/‐ mice, whereas it induced hepatic ferroportin exclusively in wild‐type mice. Conclusion: Our data show that dietary iron differentially affects ferroportin expression in mouse tissues and are consistent with hepcidin‐dependent and hepcidin‐independent mechanisms for ferroportin regulation. In the Hjv‐/‐ mouse model of hemochromatosis, duodenal ferroportin remains unresponsive to iron but DMT1 is appropriately iron‐regulated.

• SREBP
• TNFR1
• apoptosis
• caspase
• cholesterol metabolism
• iron metabolism
• lipid raft
• tumor necrosis factor (TNF)

• Ferroportin
• Hepcidin
• Iron
• Iron Regulatory Proteins 1
• Placenta
• Transferrin receptor

Hepcidin is a peptide hormone that targets the iron exporter ferroportin, thereby limiting iron entry into the bloodstream. It is generated in hepatocytes mainly in response to increased body iron stores or inflammatory cues. Iron stimulates expression of bone morphogenetic protein 6 (BMP6) from liver sinusoidal endothelial cells, which in turn binds to BMP receptors on hepatocytes and induces the SMAD signaling cascade for transcriptional activation of the hepcidin-encoding HAMP mRNA. SMAD signaling is also essential for inflammatory HAMP mRNA induction by the IL-6/STAT3 pathway. Herein, we utilized human Huh7 hepatoma cells and primary murine hepatocytes to assess the effects of iron perturbations on signaling to hepcidin. Iron chelation appeared to slightly impair signaling to hepcidin. Subsequent iron supplementation not only failed to reverse these effects, but drastically reduced basal HAMP mRNA and inhibited HAMP mRNA induction by BMP6 and/or IL-6. Thus, treatment of cells with excess iron inhibited basal and BMP6-mediated SMAD5 phosphorylation and induction of HAMP, ID1 and SMAD7 mRNAs in a dose-dependent manner. Iron also inhibited IL-6-mediated STAT3 phosphorylation and induction of HAMP and SOCS3 mRNAs. These responses were accompanied by induction of GCLC and HMOX1 mRNAs, known markers of oxidative stress. We conclude that hepatocellular iron overload suppresses hepcidin by inhibiting the SMAD and STAT3 signaling pathways downstream of their respective ligands.

• osteoporosis
• bone

• I01 BX000838 BLRD VA
• R01 AG051773 NIA NIH HHS
• U.S. Department of Veterans Affairs (Department of Veterans Affairs)

Ferroptosis is a unique regulated cell death defined by the intracellular iron overload and distinct biological features compared with other well-known programmed cell death. Ferroptosis can be triggered by many causes including decreased expression of glutathione (GSH), inhibition of the function of glutathione-dependent peroxidase 4 (GPX4), and system x_c^–, all of which finally lead to the over-accumulation of lipid peroxides in the cell. Ferroptosis has been reported to play an important role in the pathophysiological process of various cancers. In recent years, much evidence also proved that ferroptosis is involved in the progress of cerebral stroke. In this review, we summarized the characteristics of ferroptosis and the potential relationship between ferroptosis and ischemic and hemorrhagic stroke, to provide new targets and ideas for the therapy of stroke.

• ferroptosis
• glutathione inhibition
• hemorrhagic stroke
• iron overload
• ischemic stroke
• lipid peroxidation
• programmed cell death

• BMP/SMAD
• Hepcidin
• Inflammation
• Iron metabolism
• Microglia
• STAT3

• anemia
• chronic kidney disease
• erythroferrone
• fibroblast growth factor 23
• prolyl-4-hydroxylase inhibitor
• vadadustat

The relationship between hemochromatosis and diabetes has been well established, as excessive iron deposition has been reported to result in impaired function of the endocrine and exocrine pancreas. Therefore, the objective of the present study was to analyze the effects of iron accumulation on the pancreata and glucose homeostasis in a bone morphogenetic protein 6-knockout (Bmp6^−/−) mouse model of hemochromatosis. The sera and pancreatic tissues of wild-type (WT) and Bmp6^−/− mice (age, 3 and 10 months) were subjected to biochemical and histological analyses. In addition, ¹⁸F-fluorodeoxyglucose biodistribution was evaluated in the liver, muscle, heart, kidney and adipose tissue of both animal groups. The results demonstrated that 3-month-old Bmp6^−/− mice exhibited iron accumulation preferentially in the exocrine pancreas, with no signs of pancreatic injury or fibrosis. No changes were observed in the glucose metabolism, as pancreatic islet diameter, insulin and glucagon secretion, blood glucose levels and glucose uptake in the liver, muscle and adipose tissue remained comparable with those in the WT mice. Aging Bmp6^−/− mice presented with progressive iron deposits in the exocrine pancreas, leading to pancreatic degeneration and injury that was characterized by acinar atrophy, fibrosis and the infiltration of inflammatory cells. However, the aging mice exhibited unaltered blood glucose levels and islet structure, normal insulin secretion and moderately increased α-cell mass compared with those in the age-matched WT mice. Additionally, iron overload and pancreatic damage were not observed in the aging WT mice. These results supported a pathogenic role of iron overload in aging Bmp6^−/− mice leading to iron-induced exocrine pancreatic deficiency, whereas the endocrine pancreas retained normal function.

• bone morphogenetic protein 6
• glucose homeostasis
• pancreas
• iron metabolism
• diabetes

• acromegaly
• complete blood count
• erythropoiesis
• hepcidin
• iron

• Acromegaly
• Adult
• Erythropoiesis
• Hepcidins
• Homeostasis
• Humans
• Iron

• Anemia
• Bone morphogenetic protein
• Hemochromatosis
• Hemojuvelin
• Hepcidin
• Iron
• SMAD

• Animals
• Bone Morphogenetic Proteins
• Endothelial Cells
• GPI-Linked Proteins
• Hepatocytes
• Homeostasis
• Humans
• Iron

• R01 DK087727 NIDDK NIH HHS

• iron
• hepcidin
• liver
• bone morphogenetic protein
• smad

Iron deficiency anemia affects 1.2 billion people globally. Our objectives were to determine if (1) supplemental iron extracted from defatted microalgae (Nannochloropsis oceanica, DGM) and (2) a combination of minute amount of plant phytase and inulin could help replete hemoglobin in anemic mice. Mice (7 weeks old) were fed a control diet (6 mg Fe/kg). After 10 weeks, the mice were assigned to three treatments: control, control + DGM iron (Fe-DGM, 39 mg Fe/kg), or control + 1% inulin + 250 units of phytase/kg (INU−PHY, 6 mg Fe/kg). The mice had free access to diets and water for 6 weeks. The Fe-DGM group had elevated blood hemoglobin (p < 0.01) and a two-fold greater (p < 0.0001) liver non-heme iron over the control. Strikingly, the INU-PHY group had 34% greater non-heme iron than the control, despite the same concentrations of iron in their diets. Fe-DGM group had altered (p < 0.05) mRNA levels of hepcidin, divalent metal transporter 1, transferrin and transferrin receptor 1. Iron extracted from defatted microalgae seemed to be effective in alleviating moderate anemia, and INU-PHY enhanced utilization of intrinsic iron present in the rice diet. Our findings may lead to a novel formulation of these ingredients to develop safer and bioavailable iron supplements for iron-deficient populations.

• inulin
• iron bioavailability
• mice
• microalgae
• phytase
• rice-based diet

The liver is the organ for iron storage and regulation; it senses circulating iron concentrations in the body through the BMP-SMAD pathway and regulates the iron intake from food and erythrocyte recovery into the bloodstream by secreting hepcidin. Under iron deficiency, hypoxia, and hemorrhage, the liver reduces the expression of hepcidin to ensure the erythropoiesis but increases the excretion of hepcidin during infection and inflammation to reduce the usage of iron by pathogens. Excessive iron causes system iron overload; it accumulates in never system and damages neurocyte leading to neurodegenerative diseases such as Parkinson's syndrome. When some gene mutations affect the perception of iron and iron regulation ability in the liver, then they decrease the expression of hepcidin, causing hereditary diseases such as hereditary hemochromatosis. This review summarizes the source and utilization of iron in the body, the liver regulates systemic iron homeostasis by sensing the circulating iron concentration, and the expression of hepcidin regulated by various signaling pathways, thereby understanding the pathogenesis of iron-related diseases.

• HAMP
• HepG2 cells
• Hepcidin
• Iron
• Iron-sensing
• Transferrin receptor

• Antigens, CD/genetics
• Antigens, CD/metabolism
• Gene Expression/genetics
• Hep G2 Cells
• Hepatocytes/metabolism
• Hepcidins/genetics
• Hepcidins/metabolism
• Homeostasis/genetics
• Humans
• Iron/metabolism
• Receptors, Transferrin/genetics
• Receptors, Transferrin/metabolism
• Recombinant Proteins

• Antigen Presentation/physiology
• Antigens, CD1/metabolism
• Dendritic Cells/metabolism
• Humans
• Inflammation/metabolism
• Interleukin-3 Receptor alpha Subunit/metabolism
• Lectins, C-Type/metabolism
• Lymph Nodes/metabolism
• Membrane Glycoproteins/metabolism
• Receptors, Immunologic/metabolism
• Skin/metabolism

• MC_PC_15002 Medical Research Council
• MC_U105178805 Medical Research Council
• C399/A2291 Cancer Research UK
• MC_U137881017 Medical Research Council
• G1000800 Medical Research Council
• G116/150 Medical Research Council
• 17722 Cancer Research UK
• G0701693 Medical Research Council
• Wellcome Trust
• MC_UU_12010/5 Medical Research Council
• G0800158 Medical Research Council
• MR/K021222/1 Medical Research Council
• MC_U137884181 Medical Research Council
• 100963/Z/13/Z Wellcome Trust
• MC_UU_12010/1 Medical Research Council
• MC_UU_00008/1 Medical Research Council
• MC_PC_14103 Medical Research Council
• MC_UU_00008/5 Medical Research Council
• MR/K01577X/1 Medical Research Council
• Department of Health
• G0501975 Medical Research Council
• 209222/Z/17/Z Wellcome Trust
• 11331 Cancer Research UK
• MC_EX_MR/R022550/1 Medical Research Council
• MC_PC_14131 Medical Research Council
• National Institute for Health Research
• British Association of Dermatologists
• British Skin Foundation
• Misses Barrie Charitable Trust
• Oxford Biomedical Research Centre
• UCB Pharma
• European Union
• Marie Sklodowska-Curie

• child
• ferritin
• hepcidin
• pediatric reference ranges
• transferrin saturation

• iron/metabolism
• dna methylation
• histones/protein modification
• micrornas
• epigenetics
• review

• erythropoiesis
• erythropoietin
• hereditary hemochromatosis
• iron
• iron metabolism
• iron overload
• metabolic regulation
• metal homeostasis
• transferrin
• transferrin receptor-2