• FXN/NINJ1 signalling
• Ox‐mtDNA
• metformin
• mitochondrial homeostasis
• pancreatitis

• 2025ZNSFSC0051 Natural Science Foundation of Sichuan Province
• 2025ZNSFSC0584 Natural Science Foundation of Sichuan Province
• 2025ZNSFSC0700 Natural Science Foundation of Sichuan Province
• 2025ZNSFSC0938 Natural Science Foundation of Sichuan Province
• 161200012 Innovative Chinese Medicine Preclinical Research Fund of 'Liqing No.2', West China Hospital, Sichuan University

• Polycystic ovary syndrome
• hepcidin
• iron metabolism
• meta-analysis

• Polycystic Ovary Syndrome/blood
• Humans
• Hepcidins/blood
• Female
• Body Mass Index

• Chelator
• hemochromatosis
• hepcidin
• iron overload
• thalassemia

• Hepcidins/metabolism
• Humans
• Iron Overload/drug therapy
• Animals
• Molecular Targeted Therapy
• Iron/metabolism
• Cation Transport Proteins/metabolism
• Hemochromatosis/physiopathology
• Hemochromatosis/therapy
• Hemochromatosis/metabolism

• Cancer
• Cell death
• Iron
• Ischemia/reperfusion
• Lipid peroxidation
• Neurodegeneration

• Ferroptosis
• Humans
• Animals
• Iron/metabolism
• Neoplasms/metabolism
• Neoplasms/drug therapy
• Neoplasms/pathology
• Lipid Peroxidation
• Oxidation-Reduction
• Disease Susceptibility

• P30 CA008748 NCI NIH HHS
• R01 GM112948 NIGMS NIH HHS

• Ferritin
• Hepcidin
• Intra-pancreatic fat deposition
• Iron metabolism
• Magnetic resonance imaging
• Pancreas
• Pancreatitis
• Total pancreas volume

• Humans
• Hepcidins
• Pancreas/diagnostic imaging
• Liver/diagnostic imaging
• Ferritins
• Iron

• iron metabolism
• magnetic resonance imaging
• pancreas
• pancreatitis
• water protons

• Humans
• Ferritins
• Protons
• Hepcidins
• Acute Disease
• Pancreas
• Abdomen
• Pancreatitis, Chronic
• Iron

• Acinar cells
• Fibrosis
• Inflammation
• Oncogenesis
• Pancreas

• Animals
• Humans
• Acinar Cells/metabolism
• Acinar Cells/pathology
• Pancreas/metabolism
• Pancreas/pathology
• Pancreatic Diseases/metabolism
• Pancreatic Diseases/pathology
• Pancreatitis
• Chronic Disease
• Fibrosis

• Adipose tissue
• Hepcidin
• Inflammation
• Insulin resistance
• Iron
• Macrophage

• FISH
• aging
• astrocytes
• ferritin
• hemochromatosis
• hippocampus

• RNA expression
• T-cell receptor
• chronic pancreatitis
• immunology
• pancreatitis

• Disuse
• Mitochondria
• Myosin heavy chain
• Sarcopenia
• Typology

• Estradiol/pharmacology
• Estrogen Receptor alpha/genetics
• Estrogen Receptor beta/genetics
• Estrogens/metabolism
• Estrogens/pharmacology
• Humans
• Insulin-Secreting Cells/metabolism
• Iron/metabolism
• Signal Transduction

• Case report
• Hepatocyte
• Hepcidin
• Hereditary hemochromatosis
• Human placental extract
• Iron metabolism
• Iron-overloading disease
• Phlebotomy

• Adult
• Animals
• Diabetes Mellitus, Type 2/complications
• Diabetes Mellitus, Type 2/drug therapy
• Female
• Hemochromatosis/drug therapy
• Hemochromatosis/genetics
• Humans
• Male
• Pharmaceutical Preparations
• Phlebotomy
• Placenta
• Pregnancy
• Swine

• disordered iron metabolism
• iron metabolism
• macrophage polarization

• Animals
• Homeostasis
• Humans
• Inflammation/immunology
• Inflammation/metabolism
• Iron/immunology
• Iron/metabolism
• Macrophage Activation
• Macrophages/immunology
• Macrophages/metabolism
• Phagocytosis

• Anaemia of chronic disease
• Hepcidin
• diagnosis
• meta-analysis

• Anemia/blood
• Anemia/diagnosis
• Chromatography, Liquid/methods
• Chronic Disease
• Enzyme-Linked Immunosorbent Assay/methods
• Hepcidins/blood
• Humans
• Mass Spectrometry/methods
• ROC Curve

• Animals
• Ceruletide/metabolism
• Cholecystokinin/metabolism
• Disease Models, Animal
• Extracellular Matrix/metabolism
• Female
• Gene Expression Profiling
• Gene Expression Regulation
• Male
• Mice
• Mice, Inbred C57BL
• Pancreas/metabolism
• Pancreatitis, Chronic/metabolism
• Pancreatitis, Chronic/therapy
• RNA-Seq
• Signal Transduction
• Transcriptome

• R21 AA027014 NIAAA NIH HHS

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

• Exocrine pancreas
• Exocrine pancreatic dysfunction
• Ferritin
• Hepcidin
• Iron
• Pancreatitis

Based on the evidence that hemochromatosis, an iron-overload disease, drives hepatocellular carcinoma, we hypothesized that chronic exposure to excess iron, either due to genetic or environmental causes, predisposes an individual to cancer. Using pancreatic cancer as our primary focus, we employed cell culture studies to interrogate the connection between excess iron and cancer, and combined in vitro and in vivo studies to explore the connection further. Ferric ammonium citrate was used as an exogenous iron source. Chronic exposure to excess iron induced epithelial-mesenchymal transition (EMT) in normal and cancer cell lines, loss of p53, and suppression of p53 transcriptional activity evidenced from decreased expression of p53 target genes (p21, cyclin D1, Bax, SLC7A11). To further extrapolate our cell culture data, we generated EL-Kras^G12D (EL-Kras) mouse (pancreatic neoplastic mouse model) expressing Hfe^+/+and Hfe^−/− genetic background. p53 target gene expression decreased in EL-Kras/Hfe^−/− mouse pancreas compared to EL-Kras/Hfe^+/+ mouse pancreas. Interestingly, the incidence of acinar-to-ductal metaplasia and cystic pancreatic neoplasms (CPN) decreased in EL-Kras/Hfe^−/− mice, but the CPNs that did develop were larger in these mice than in EL-Kras/Hfe^+/+ mice. In conclusion, these in vitro and in vivo studies support a potential role for chronic exposure to excess iron as a promoter of more aggressive disease via p53 loss and SLC7A11 upregulation within pancreatic epithelial cells.

• Epithelial-mesenchymal transition
• Heme
• Iron
• SLC7A11
• p53

• pancreatitis
• ngal
• acinar cells
• endothelial cells
• reactive oxygen species

• Hic-5
• NF-κB
• chronic pancreatitis
• pancreatic stellate cells
• triptolide

• brain iron metabolism
• hepcidin
• neurodegenerative diseases
• neuroferritinopathy and aceruloplasminemia
• reduction in brain iron
• therapeutic potential

Hepcidin is the hyposideremic hormone regulating iron metabolism. It is a defensin-like disulfide-bonded peptide with antimicrobial activity. The main site of hepcidin production is the liver where its synthesis is modulated by iron, inflammation and erythropoietic signaling. However, hepcidin locally produced in several peripheral organs seems to be an important actor for the maintenance of iron homeostasis in these organs. This review highlights the presence of peripheral hepcidin and its potential functions. Understanding the role of extrahepatic hepcidin could be of great physiological and therapeutic importance for several specific pathologies.

• Hepcidin
• Extrahepatic hepcidin
• Iron metabolism
• Bacterial infection
• Inflammation

Hepcidin is an acute-phase protein involved also in regulation of iron homeostasis. The aim of the study was to prospectively assess for the first time the hepcidin_EL concentration in patients with subacute thyroiditis (SAT), to identify biochemical determinants of hepcidin_EL concentration and evaluate the potential role of hepcidin in SAT diagnosis and monitoring.

Out of 40 patients with SAT initially recruited, restrictive inclusion criteria fulfilled 21 subjects aged 45 ± 10 years and 21 healthy control subjects (CS). Hepcidin_EL concentration, thyroid status, and iron homeostasis were evaluated at SAT diagnosis and following therapy and compared with CS.

The median hepcidin_EL concentration at SAT diagnosis is higher than that in CS (48.8 (15.9-74.5) ng/mL vs. 18.2 (10.2-23.3) ng/mL, p = 0.009) and is significantly lower after treatment (4.0 (1.2-10.0) ng/mL, p = 0.007) compared with CS. The ROC analysis for hepcidin_EL at SAT diagnosis revealed that area under the curve (AUC) is 0.735 (p = 0.009), and the cut-off for hepcidin_EL concentration is 48.8 ng/mL (sensitivity 0.52 and specificity 0.95). Hepcidin_EL in SAT patients correlated with CRP (r = 0.614, p = 0.003), ferritin (r = 0.815, p < 0.001), and aTPO (r = -0.491, p = 0.024). On multiple regression, the correlation between hepcidin_EL and ferritin was confirmed (p < 0.001).

SAT is accompanied by a significant increase in hepcidin, which reflects an acute-phase inflammatory process. Parameters of iron homeostasis improved significantly while inflammatory indices got lower following recovery. The potential role of hepcidin as a predictive factor of the risk of SAT relapse needs to be assessed in studies on larger groups of SAT patients.

• aceruloplasminemia
• ceruloplasmin
• diabetes
• ferroxidase
• iron chelation
• iron overload
• neurodegeneration
• plasma

Hepcidin is a key hormonal regulator of systemic iron homeostasis and its expression is induced by iron or inflammatory stimuli. Genetic defects in iron signaling to hepcidin lead to “hepcidinopathies” ranging from hereditary hemochromatosis to iron-refractory iron deficiency anemia, which are disorders caused by hepcidin deficiency or excess, respectively. Moreover, dysregulation of hepcidin is a pathogenic cofactor in iron-loading anemias with ineffective erythropoiesis and in anemia of inflammation. Experiments with preclinical animal models provided evidence that restoration of appropriate hepcidin levels can be used for the treatment of these conditions. This fueled the rapidly growing field of hepcidin therapeutics. Several hepcidin agonists and antagonists, as well as inducers and inhibitors of hepcidin expression have been identified to date. Some of them were further developed and are currently being evaluated in clinical trials. This review summarizes the state of the art.

• anemia
• ferroportin
• hemochromatosis
• hepcidin
• iron metabolism

Little is known about the iron efflux from the pancreas, but it is likely that multicopper ferroxidases (MCFs) are involved in this process. We thus used hephaestin (Heph) and ceruloplasmin (Cp) single-knockout mice and Heph/Cp double-knockout mice to investigate the roles of MCFs in pancreatic iron homeostasis. We found that both HEPH and CP were expressed in the mouse pancreas, and that ablation of either MCF had limited effect on the pancreatic iron levels. However, ablation of both MCFs together led to extensive pancreatic iron deposition and severe oxidative damage. Perls’ Prussian blue staining revealed that this iron deposition was predominantly in the exocrine pancreas, while the islets were spared. Consistent with these results, plasma lipase and trypsin were elevated in Heph/Cp knockout mice, indicating damage to the exocrine pancreas, while insulin secretion was not affected. These data indicate that HEPH and CP play mutually compensatory roles in facilitating iron efflux from the exocrine pancreas, and show that MCFs are able to protect the pancreas against iron-induced oxidative damage.

• Ceruloplasmin
• Hephaestin
• Iron efflux
• Multicopper ferroxidase
• Oxidative damage
• Pancreas

(1) Background: Iron requirement increases during pregnancy and iron supplementation is therefore recommended in many countries. However, excessive iron intake may lead to destruction of pancreatic β-cells. Therefore, we aim to test if higher neonatal iron content in blood is associated with the risk of developing type 1 diabetes mellitus (T1D) in childhood; (2) Methods: A case-control study was conducted, including 199 children diagnosed with T1D before the age of 16 years from 1991 to 2005 and 199 controls matched on date of birth. Information on confounders was available in 181 cases and 154 controls. Iron was measured on a neonatal single dried blood spot sample and was analyzed by laser ablation inductively coupled plasma mass spectrometry. Multivariate logistic regression was used to evaluate if iron content in whole blood was associated with the risk of T1D; (3) Results: A doubling of iron content increased the odds of developing T1D more than two-fold (odds ratio (95% CI), 2.55 (1.04; 6.24)). Iron content increased with maternal age (p = 0.04) and girls had higher content than boys (p = 0.01); (4) Conclusions: Higher neonatal iron content associates to an increased risk of developing T1D before the age of 16 years. Iron supplementation during early childhood needs further investigation, including the causes of high iron in neonates.

• diabetes mellitus
• embryonic and fetal development
• iron
• newborn
• pediatrics
• type 1

• Adolescent
• Case-Control Studies
• Child
• Child, Preschool
• Diabetes Mellitus, Type 1/blood
• Female
• Humans
• Infant
• Infant, Newborn
• Iron/blood
• Male
• Odds Ratio
• Risk Factors

Pulmonary iron excess is deleterious and contributes to a range of chronic and acute inflammatory diseases. Optimal lung iron concentration is maintained through dynamic regulation of iron transport and storage proteins. The iron-regulatory hormone hepcidin is also expressed in the lung. In order to better understand the interactions between iron-associated molecules and the hepcidin-ferroportin axis in lung iron balance, we examined lung physiology and inflammatory responses in two murine models of systemic iron-loading, either hepcidin knock-out (Hepc KO) or liver-specific hepcidin KO mice (Hepc KOliv), which do (Hepc KOliv) or do not (Hepc KO) express lung hepcidin. We have found that increased plasma iron in Hepc KO mice is associated with increased pulmonary iron levels, consistent with increased cellular iron uptake by pulmonary epithelial cells, together with an increase at the apical membrane of the cells of the iron exporter ferroportin, consistent with increased iron export in the alveoli. Subsequently, alveolar macrophages (AM) accumulate iron in a non-toxic form and this is associated with elevated production of ferritin. The accumulation of iron in the lung macrophages of hepcidin KO mice contrasts with splenic and hepatic macrophages which contain low iron levels as we have previously reported. Hepc KOliv mice with liver-specific hepcidin deficiency demonstrated same pulmonary iron overload profile as the Hepc KO mice, suggesting that pulmonary hepcidin is not critical in maintaining local iron homeostasis. In addition, the high iron load in the lung of Hepc KO mice does not appear to enhance acute lung inflammation or injury. Lastly, we have shown that intraperitoneal LPS injection is not associated with pulmonary hepcidin induction, despite high levels of inflammatory cytokines. However, intranasal LPS injection stimulates a hepcidin response, likely derived from AM, and alters pulmonary iron content in Hepc KO mice.

• alveolar macrophages
• ferritin
• ferroportin
• hepcidin
• inflammation
• iron
• lung
• mouse model

• type 1 diabetes
• iron overload
• iron intake
• risk factor
• insulin
• systematic review

• Diabetes Mellitus, Type 1/etiology
• Diet
• Humans
• Insulin/metabolism
• Iron/adverse effects
• Iron, Dietary/adverse effects
• Risk
• Water Supply