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Iron delivery to the plasma is closely coupled to erythropoiesis, the production of red blood cells, as this process consumes most of the circulating plasma iron. In response to hemorrhage and other erythropoietic stresses, increased erythropoietin stimulates the production of the hormone erythroferrone (ERFE) by erythrocyte precursors (erythroblasts) developing in erythropoietic tissues. ERFE acts on the liver to inhibit bone morphogenetic protein (BMP) signaling and thereby decrease hepcidin production. Decreased circulating hepcidin concentrations then allow the release of iron from stores and increase iron absorption from the diet. Guided by evolutionary analysis and Alphafold2 protein complex modeling, we used targeted ERFE mutations, deletions, and synthetic ERFE segments together with cell-based bioassays and surface plasmon resonance to probe the structural features required for bioactivity and BMP binding. We define the ERFE active domain and multiple structural features that act together to entrap BMP ligands. In particular, the hydrophobic helical segment 81 to 86 and specifically the highly conserved tryptophan W82 in the N-terminal region are essential for ERFE bioactivity and Alphafold2 modeling places W82 between two tryptophans in its ligands BMP2, BMP6, and the BMP2/6 heterodimer, an interaction similar to those that bind BMPs to their cognate receptors. Finally, we identify the cationic region 96-107 and the globular TNFα-like domain 186-354 as structural determinants of ERFE multimerization that increase the avidity of ERFE for BMP ligands. Collectively, our results provide further insight into the ERFE-mediated inhibition of BMP signaling in response to erythropoietic stress.

Exercise-induced inflammation can influence iron metabolism. Conversely, the effects of vitamin D3, which possesses anti-inflammatory properties, on ultramarathon-induced heart damage and changes in iron metabolism have not been investigated. Thirty-five healthy long-distance semi-amateur runners were divided into two groups: one group received 150,000 IU of vitamin D3 24 h prior to a race (n = 16), while the other group received a placebo (n = 19). Serum iron, hepcidin (HPC), ferritin (FER), erythroferrone (ERFE), erythropoietin (EPO), neopterin (NPT), and cardiac troponin T (cTnT) levels were assessed. A considerable effect of ultramarathon running on all examined biochemical markers was observed, with a significant rise in serum levels of ERFE, EPO, HPC, NPT, and cTnT detected immediately post-race, irrespective of the group factor. Vitamin D3 supplementation showed a notable interaction with the UM, specifically in EPO and cTnT, with no other additional changes in the other analysed markers. In addition to the correlation between baseline FER and post-run ERFE, HPC was modified by vitamin D. The ultramarathon significantly influenced the EPO/ERFE/HPC axis; however, a single substantial dose of vitamin D3 had an effect only on EPO, which was associated with the lower heart damage marker cTnT after the run. [ABSTRACT FROM AUTHOR]

Background: Currently, erythroferrone (ERFE) has been discovered to be involved in iron control and erythropoiesis. Objective: To investigate cord blood erythroferrone level and iron status in neonates with high risk factors and correlate these factors to the development of iron deficiency anemia at birth. Patients and methods: This is a prospective study that was conducted on neonates recruited from the Obstetrics and Gynecology Department, Faculty of Medicine, Menoufia University and Neonatal Intensive Care Unit (NICU) during the period from January 2023 to March 2024. The participants underwent full history taking, clinical examination, and laboratory investigations including iron profile and erythroferrone. Results: The mean serum iron and ferritin levels exhibited significant differences among the groups (p<0.001), with the lowest mean values were shown in the neonates of iron deficient mothers. Total iron binding capacity (TIBC) and cord blood erythroferrone levels showed a statistically significant difference among the groups (p<0.001), with the highest mean value was shown in the neonates of iron deficient mothers. ROC analysis showed that ERFE had high area under the curves (AUCs) to differentiate neonates of iron-deficient mothers (0.974, p <0.001) and low-birth-weight neonates (0.953, p<0.001) from the control group. Conclusion: Our findings indicate that neonates of iron-deficient mothers and those with low birth weight exhibit elevated ERFE levels, highlighting the potential of ERFE as a biomarker for diagnosing iron deficiency anemia in highrisk neonates, as demonstrated by the excellent performance of ERFE levels in distinguishing affected neonates from healthy controls. This underscores the clinical relevance of ERFE in neonatal care and its potential as a therapeutic target. [ABSTRACT FROM AUTHOR]

Myelodysplastic neoplasms (MDS) are a heterogenous group of clonal stem cell disorders characterized by dysplasia and cytopenia in one or more cell lineages. Anemia is a very common symptom that is often treated with blood transfusions and/or erythropoiesis stimulating factors. Iron overload results from a combination of these factors together with the disease-associated ineffective erythropoiesis, that is seen especially in MDS cases with SF3B1 mutations. A growing body of research has shown that erythroferrone is an important regulator of hepcidin, the master regulator of systemic iron homeostasis. Consequently, it is of interest to understand how this molecule contributes to regulating the iron balance in MDS patients. This short review evaluates our current understanding of erythroferrone in general, but more specifically in MDS and seeks to place in context how the current knowledge could be utilized for prognostication and therapy. [ABSTRACT FROM AUTHOR]

Purpose: Inflammatory cytokines including interleukin-6 can upregulate hepcidin and decrease iron absorption. Endurance exercise is associated with transient increases in cytokines, which may alter the risk of iron deficiency (ID). This study examined whether chronic elevations in basal levels of cytokines and hepcidin were associated with ID in highly trained runners. Methods: Fifty-four collegiate runners (26 males and 28 females) living at ∼1625 m were recruited from an NCAA Division I cross-country team for this prospective cohort study. Over 2 seasons, fasted, preexercise blood draws were performed in the morning 4 times per season and were analyzed for hemoglobin concentration, ferritin, soluble transferrin receptor (sTfR), hepcidin, and 10 cytokines. Stages of ID were defined using ferritin, sTfR, and hemoglobin concentration. During the study, a registered dietician provided all runners with iron supplements using athletic department–created guidelines. Results: Fifty-seven percent of females and 35% of males exhibited stage 2 ID (ferritin <20 ng/mL or sTfR >29.5 nmol/L) at least once. Cytokines, ferritin, and sTfR exhibited changes through the 2 years, but changes in cytokines were not associated with alterations in hepcidin, ferritin, or sTfR. In males and females, lower ferritin was associated with lower hepcidin (both P <.0001). One female exhibited higher hepcidin and lower iron stores compared with other individuals, suggesting a different etiology of ID. Conclusion: ID is common in highly trained collegiate runners. In general, the high prevalence of ID in this population is not associated with alterations in basal hepcidin or cytokine levels. [ABSTRACT FROM AUTHOR]

Abstract Background Iron deficiency anemia remains a significant public health issue in developing countries. The regulation of iron metabolism is primarily controlled by hepcidin, a key regulatory protein. During erythropoiesis, erythroferrone (ERFE), a hormone produced by erythroblasts in response to erythropoietin (EPO) synthesis, mediates the suppression of hepcidin. In this study, it was aimed to determine the correlation between erythroferrone (ERFE) and hepcidin levels in children with iron deficiency anemia. Methods This is a case-control study conducted at Kırşehir Ahi Evran University Training and Research Hospital Pediatrics Clinic between 1 and 31 September 2020. The study included 26 healthy children and 26 children with iron deficiency anemia. In order to evaluate iron status,whole blood count, serum iron, total iron binding capacity (TIBC), and ferritin levels were analyzed. The study measured the levels of hepcidin and erythroferrone in the serum of children diagnosed with iron deficiency before and after one month of iron treatment, as well as in a control group, using the ELISA method. Correlation between whole blood count, initial ferritin, hepcidin, ERFE and ferritin in the iron deficiency group was evaluated. Results Compared with healthy controls, the iron-deficient group had significantly lower haemoglobin (p

Background: Iron deficiency anemia remains a significant public health issue in developing countries. The regulation of iron metabolism is primarily controlled by hepcidin, a key regulatory protein. During erythropoiesis, erythroferrone (ERFE), a hormone produced by erythroblasts in response to erythropoietin (EPO) synthesis, mediates the suppression of hepcidin. In this study, it was aimed to determine the correlation between erythroferrone (ERFE) and hepcidin levels in children with iron deficiency anemia. Methods: This is a case-control study conducted at Kırşehir Ahi Evran University Training and Research Hospital Pediatrics Clinic between 1 and 31 September 2020. The study included 26 healthy children and 26 children with iron deficiency anemia. In order to evaluate iron status,whole blood count, serum iron, total iron binding capacity (TIBC), and ferritin levels were analyzed. The study measured the levels of hepcidin and erythroferrone in the serum of children diagnosed with iron deficiency before and after one month of iron treatment, as well as in a control group, using the ELISA method. Correlation between whole blood count, initial ferritin, hepcidin, ERFE and ferritin in the iron deficiency group was evaluated. Results: Compared with healthy controls, the iron-deficient group had significantly lower haemoglobin (p < 0.001), MCV (p = 0.001), MCH (p < 0.001), MCHC (p < 0.001), iron (p < 0.001), ferritin (p < 0.001) and hepcidin (p = 0.001). Ferritin and hepcidin levels increased while erythroferrone levels remained unchanged after iron deficiency treatment. There was no correlation between hepcidin and ferritin levels in treatment group. Conclusions: The study found a strong and positive correlation between ferritin and hepcidin levels in iron-deficient children, but not between ERFE levels, suggesting that hepcidin is largely regulated by iron deposition levels. In addition, there was an increase in ferritin and hepcidin levels after iron treatment. The study found no significant difference in erythroferrone levels between the iron-deficient group and the control group. It is thought that this may be due to the short duration of iron treatment given to the patients with iron deficiency anemia included in the study. [ABSTRACT FROM AUTHOR]

Purpose: The effectiveness of altitude training on haematological adaptations is largely dependent on iron metabolism. Hepcidin and erythroferrone (ERFE) are key iron-regulating hormones, yet their response to altitude training is poorly understood. The aim of this study was to analyze changes in hepcidin and ERFE under the influence of 3 weeks of the Live High-Train Low (LH-TL) method. Methods: Twenty male trained cyclists completed a 3-week training program under normoxic conditions (NORM) or with passive exposure to normobaric hypoxia (LH-TL; FiO2 = 16.5%, ~2000 m; 11-12 h/day). Hepcidin, ERFE, hypoxia inducible factor-2 (HIF-2), ferroportin (Fpn), erythropoietin (EPO), serum iron (Fe) and hematological variables were assessed at baseline (S1), then immediately after (S2) and 3 days after (S3) intervention. Results: In the LH-TL group, hepcidin decreased by 13.0% (p < 0.001) in S2 and remained at a reduced level in S3. ERFE decreased by 28.7% (p < 0.05) in S2 and returned to baseline in S3. HIF-2a decreased gradually, being lower by 25.3% (p < 0.05) in S3. Fpn decreased between S1 and S2 by 18.9% (p < 0.01) and remained lower during S3 (p < 0.01). In the NORM group, in turn, hepcidin levels increased gradually, being higher by 73.9% (p < 0.05) in S3 compared to S1. No statistically significant differences in EPO were observed in both groups. Conclusion: Three weeks of LH-TL suppresses resting hepcidin and ERFE levels in endurance athletes. We found no association between hepcidin and ERFE after LH-TL. Probably, ERFE is not the only factor that suppresses hepcidin expression in response to moderate hypoxia, especially in later stages of hepcidin downregulation. With the cessation of hypoxia, favorable conditions for increasing the availability of iron cease. [ABSTRACT FROM AUTHOR]

Myelodysplastic neoplasms (MDS) are a heterogenous group of clonal stem cell disorders characterized by dysplasia and cytopenia in one or more cell lineages. Anemia is a very common symptom that is often treated with blood transfusions and/or erythropoiesis stimulating factors. Iron overload results from a combination of these factors together with the disease-associated ineffective erythropoiesis, that is seen especially in MDS cases with SF3B1 mutations. A growing body of research has shown that erythroferrone is an important regulator of hepcidin, the master regulator of systemic iron homeostasis. Consequently, it is of interest to understand how this molecule contributes to regulating the iron balance in MDS patients. This short review evaluates our current understanding of erythroferrone in general, but more specifically in MDS and seeks to place in context how the current knowledge could be utilized for prognostication and therapy.

Exercise-induced inflammation can influence iron metabolism. Conversely, the effects of vitamin D3, which possesses anti-inflammatory properties, on ultramarathon-induced heart damage and changes in iron metabolism have not been investigated. Thirty-five healthy long-distance semi-amateur runners were divided into two groups: one group received 150,000 IU of vitamin D3 24 h prior to a race (n = 16), while the other group received a placebo (n = 19). Serum iron, hepcidin (HPC), ferritin (FER), erythroferrone (ERFE), erythropoietin (EPO), neopterin (NPT), and cardiac troponin T (cTnT) levels were assessed. A considerable effect of ultramarathon running on all examined biochemical markers was observed, with a significant rise in serum levels of ERFE, EPO, HPC, NPT, and cTnT detected immediately post-race, irrespective of the group factor. Vitamin D3 supplementation showed a notable interaction with the UM, specifically in EPO and cTnT, with no other additional changes in the other analysed markers. In addition to the correlation between baseline FER and post-run ERFE, HPC was modified by vitamin D. The ultramarathon significantly influenced the EPO/ERFE/HPC axis; however, a single substantial dose of vitamin D3 had an effect only on EPO, which was associated with the lower heart damage marker cTnT after the run.

BackgroundIn pediatric kidney transplant recipients, anemia is common and oftentimes multifactorial. Hemoglobin concentrations may be affected by traditional factors, such as kidney function and iron status, as well as novel parameters, such as fibroblast growth factor 23 (FGF23).MethodsHere, we evaluated associations among erythropoietic, iron-related, and FGF23 parameters in a cohort of pediatric kidney transplant recipients, hypothesizing that multiple factors are associated with hemoglobin concentrations.ResultsIn a cross-sectional analysis of 59 pediatric kidney transplant recipients (median (interquartile range) age 16.3 (13.5, 18.6) years, median estimated glomerular filtration rate (eGFR) 67 (54, 87) ml/min/1.73 m2), the median age-related hemoglobin standard deviation score (SDS) was -2.1 (-3.3, -1.1). Hemoglobin SDS was positively associated with eGFR and calcium, and was inversely associated with erythropoietin (EPO), mycophenolate dose, and total, but not intact, FGF23. In multivariable analysis, total FGF23 remained inversely associated with hemoglobin SDS, independent of eGFR, iron parameters, EPO, and inflammatory markers, suggesting a novel FGF23-hemoglobin association in pediatric kidney transplant patients. In a subset of patients with repeat measurements, only delta hepcidin was inversely associated with delta hemoglobin SDS. Also, delta EPO positively correlated with delta erythroferrone (ERFE), and delta ERFE inversely correlated with delta hepcidin, suggesting a possible physiologic role for the EPO-ERFE-hepcidin axis in the setting of chronic kidney disease (CKD).ConclusionOur study provides further insight into factors potentially associated with erythropoiesis in pediatric kidney transplant recipients. A higher resolution version of the Graphical abstract is available as Supplementary information.

ObjectivesIn dyspneic patients with atrial fibrillation (AF) or obesity, the diagnostic performance of NT-proBNP for acute heart failure is reduced. We evaluated the erythroblast derived protein erythroferrone (ERFE) as an ancillary biomarker for the diagnosis of acute decompensated heart failure (ADHF) in these comorbid subgroups in both Western and Asian populations.MethodsThe diagnostic performance of ERFE (Intrinsic Lifesciences) and NT-proBNP (Roche Cobas e411) for ADHF was assessed in 479 New Zealand (NZ) and 475 Singapore (SG) patients presenting with breathlessness.ResultsPlasma ERFE was higher in ADHF, compared with breathlessness from other causes, in both countries (NZ; 4.9 vs. 1.4 ng/ml, p

β−Thalassemia patients suffer from ineffective erythropoiesis and increased red blood cell (RBC) hemolysis. Blood transfusion, erythropoietic enhancement, and antioxidant supplementation can ameliorate chronic anemia. Green tea extract (GTE) is comprised of catechin derivatives, of which epigallocatechin−3−gallate (EGCG) is the most abundant, presenting free−radical scavenging, iron−chelating, and erythropoiesis−protective effects. The present study aimed to evaluate the effects of GTE tablets on the primary outcome of erythropoiesis and oxidative stress parameters in transfusion−dependent β−thalassemia (TDT) patients. Twenty−seven TDT patients were randomly divided into placebo and GTE tablet (50 and 100 mg EGCG equivalent) groups and assigned to consume the product once daily for 60 days. Blood was collected for analysis of hematological, biochemical, and oxidative stress parameters. Accordingly, consumption of GTE tablets improved blood hemoglobin levels when compared with the placebo; however, there were more responders to the GTE tablets. Interestingly, amounts of nonheme iron in RBC membranes tended to decrease in both GTE tablet groups when compared with the placebo. Importantly, consumption of GTE tablets lowered plasma levels of erythroferrone (p < 0.05) and reduced bilirubin non−significantly and dose−independently. Thus, GTE tablets could improve RBC hemolysis and modulate erythropoiesis regulators in transfusion−dependent thalassemia patients.

Cigarette smoking is one of the leading causes of lung and blood cancers worldwide. A higher risk of pulmonary injury is associated with elevated lung iron and ferritin levels. Erythroferrone (ERFE) is a newly discovered tumor necrosis factor (TNF) superfamily member produced by erythroblasts during erythropoiesis. Eventually, it suppresses hepcidin during enhanced erythropoietic activity. The current study investigated the relationship between serum ferritin, iron, and erythroferrone concentrations among adult smokers. This study included 76 selected adult cigarette smokers and 48 healthy individuals (non-smokers) as a control group. The enzyme-linked immunosorbent assay (ELISA) and chemiluminescent immunoassay (CLIA) biochemical techniques were used to accurately measure serum iron, ferritin, and erythroferrone. Cigarette smokers (CS) had a mean age of 42.75±2.92 years, while healthy control (HC) subjects had a mean age of 37.36±2.7 years. The findings have shown a significant increase in serum iron, ferritin, and EREF levels in CS (119± 4.30, 131.1±6.58, and 75.02±2.09) compared with HC (98.67±7.84, 85.50±4.12, and 65.74±2.25) respectively. This study has shown a significant positive correlation between serum EREF (P=0.0072, r=0.4089) and the duration of smoking <20 years and a moderate association between serum iron (P=0.1907, r=0.4511) and the duration of smoking <40 years. For the first time, this outcome shows increased serum EREF and overexpression by erythroblasts in subjects associated with smoking habits, along with increased serum iron and ferritin levels. An indicative correlation is found between EREF overexpression, iron overload, and hyperferritinemia with reference to the duration of smoking. The study also illustrates the interconnection between iron metabolism perturbations and ERFE overexpression induced by cigarette smoking. [ABSTRACT FROM AUTHOR]

In recent years, a steady increase in the incidence of inflammatory bowel diseases (IBD) has been observed with anemia as their most common extraintestinal symptom. Erythroferrone and Bone Morphogenetic Protein 6 (BMP-6) are recently identified cytokines involved in the process of increased erythropoiesis in anemia of various pathomechanisms. The aim of this study was to analyze the concentration of erythroferrone and BMP-6 in IBD patients in relation to clinical and laboratory data. The study comprised 148 patients: 118 with IBD, including 73 (61.85%) diagnosed with anemia (42 with Crohn's disease (CD) (66.7%) and 31 (56.4%) with ulcerative colitis (UC)) and 30 as a control group. The erythroferrone concentration was significantly higher in IBD patients with anemia (p = 0.009) and higher in UC patients both with and without anemia (p = 0.018), compared to the control group. In CD, no similar difference was observed between patients with and without anemia. Regarding BMP-6, higher levels were found in CD patients with anemia compared to the control group (p = 0.021). The positive correlation between BMP-6 and iron concentration in UC was also noticed. In conclusion, we confirm an increase in erythroferrone concentration in the entire group of IBD patients with anemia, while BMP-6 levels were higher only in anemic CD patients. Due to the clinical importance of anemia in IBD, this problem is worth further analysis and research projects. [ABSTRACT FROM AUTHOR]

Erythroferrone (ERFE) is the main erythroid regulator of hepcidin, the homeostatic hormone controlling plasma iron levels and total body iron. When the release of erythropoietin from the kidney stimulates the production of new red blood cells, it also increases the synthesis of ERFE in bone marrow erythroblasts. Increased ERFE then suppresses hepcidin synthesis, thereby mobilizing cellular iron stores for use in heme and hemoglobin synthesis. Recent mechanistic studies have shown that ERFE suppresses hepcidin transcription by inhibiting bone morphogenetic protein signaling in hepatocytes. In ineffective erythropoiesis, pathological overproduction of ERFE by an expanded population of erythroblasts suppresses hepcidin and causes iron overload, even in non-transfused patients. ERFE may be a useful biomarker of ineffective erythropoiesis and an attractive target for treating its systemic effects.

BACKGROUND: This study aimed to determine associations among short- and long-acting erythropoiesis stimulating agents (ESAs), changes in serum fibroblast growth factor 23 (FGF23) and biomarkers of iron metabolism. METHODS: Among 108 patients on hemodialysis (HD), 44 received every 2 weeks or monthly doses of continuous erythropoiesis receptor activator (CERA), 31 received weekly doses of darbepoetin-α, 24 received three doses per week of epoetin-β and 9 were not treated with an ESA. Intact and C-terminal FGF23 and transferrin saturation (TSAT), ferritin, erythroferrone and hepcidin 25 were measured in blood samples collected before the HD session at the end of the dialysis week (baseline, Day 0) and on Days 3, 5, 7 and 14 thereafter. RESULTS: Levels of ferritin, hepcidin 25 and erythroferrone as well as TSAT were significantly decreased or elevated in patients treated with CERA compared with other types of ESAs. Levels of C-terminal FGF23 increased in all groups during the observation period. Levels of intact FGF23 and ratios of intact FGF23 to C-terminal FGF23 gradually decreased between Days 3 and 7 in the CERA but not in the other groups. Multivariate models associated changes in hepcidin 25 and phosphate with those of intact FGF23. CONCLUSION: The long-acting ESA CERA might influence levels of intact FGF23 by increasing FGF23 cleavage in patients on HD in association with prolonged hepcidin 25 suppression.

Purpose: The effectiveness of altitude training on haematological adaptations is largely dependent on iron metabolism. Hepcidin and erythroferrone (ERFE) are key iron-regulating hormones, yet their response to altitude training is poorly understood. The aim of this study was to analyze changes in hepcidin and ERFE under the influence of 3 weeks of the Live High-Train Low (LH-TL) method.Methods: Twenty male trained cyclists completed a 3-week training program under normoxic conditions (NORM) or with passive exposure to normobaric hypoxia (LH-TL; FiO2 = 16.5%, ∼2000 m; 11–12 h/day). Hepcidin, ERFE, hypoxia inducible factor-2 (HIF-2), ferroportin (Fpn), erythropoietin (EPO), serum iron (Fe) and hematological variables were assessed at baseline (S1), then immediately after (S2) and 3 days after (S3) intervention.Results: In the LH-TL group, hepcidin decreased by 13.0% (p < 0.001) in S2 and remained at a reduced level in S3. ERFE decreased by 28.7% (p < 0.05) in S2 and returned to baseline in S3. HIF-2α decreased gradually, being lower by 25.3% (p < 0.05) in S3. Fpn decreased between S1 and S2 by 18.9% (p < 0.01) and remained lower during S3 (p < 0.01). In the NORM group, in turn, hepcidin levels increased gradually, being higher by 73.9% (p < 0.05) in S3 compared to S1. No statistically significant differences in EPO were observed in both groups.Conclusion: Three weeks of LH-TL suppresses resting hepcidin and ERFE levels in endurance athletes. We found no association between hepcidin and ERFE after LH-TL. Probably, ERFE is not the only factor that suppresses hepcidin expression in response to moderate hypoxia, especially in later stages of hepcidin downregulation. With the cessation of hypoxia, favorable conditions for increasing the availability of iron cease.

Congenital erythrocytoses represent a heterogenous group of rare defects of erythropoiesis characterized by elevated erythrocyte mass. We performed molecular‐genetic analysis of 21 Czech patients with congenital erythrocytosis and assessed the mutual link between chronic erythrocyte overproduction and iron homoeostasis. Causative mutations in erythropoietin receptor (EPOR), hypoxia‐inducible factor 2 alpha (HIF2A) or Von Hippel–Lindau (VHL) genes were detected in nine patients, including a novel p.A421Cfs*4 EPOR and a homozygous intronic c.340+770T>C VHL mutation. The association and possible cooperation of five identified missense germline EPOR or Janus kinase 2 (JAK2) variants with other genetic/non‐genetic factors in erythrocytosis manifestation may involve variants of Piezo‐type mechanosensitive ion channel component 1 (PIEZO1) or Ten‐eleven translocation 2 (TET2), but this requires further research. In two families, hepcidin levels appeared to prevent or promote phenotypic expression of the disease. No major contribution of heterozygous haemochromatosis gene (HFE) mutations to the erythrocytic phenotype or hepcidin levels was observed in our cohort. VHL‐ and HIF2A‐mutant erythrocytosis showed increased erythroferrone and suppressed hepcidin, whereas no overproduction of erythroferrone was detected in other patients regardless of molecular defect, age or therapy. Understanding the interplay between iron metabolism and erythropoiesis in different subgroups of congenital erythrocytosis may improve current treatment options. [ABSTRACT FROM AUTHOR]

Thalassemia is a disease of erythrocytes that varies largely on its genetic composition and associated clinical presentation. Though some patients may remain asymptomatic, those with a complicated course may experience severe anemia early in childhood, carrying into adulthood and requiring recurrent blood transfusions as a pillar of symptom management. Due to the consequences of ineffective erythropoiesis and frequent transfusions, patients with severe beta thalassemia may be subsequently susceptible to hemochromatosis. In light of the established role of hepcidin and erythroferrone in the pathogenesis of beta thalassemia, this review aims to discuss current clinical trials and studies in the field while presenting clinical implications of the HAMP gene polymorphisms and novel treatments. Research suggested incorporating erythroferrone and serum hepcidin testing as a part of routine workups for beta thalassemia, as they could be a predictive tool for early iron accumulation. Furthermore, ameliorating low hepcidin and high erythroferrone appeared to be crucial in treating beta thalassemia and its complications due to iron overload. Currently, hepcidin-like compounds, such as minihepcidins, LJPC-401, PTG-300, VIT-2763, and agents that promote hepcidin production by inhibiting TMPRSS6 expression or erythroferrone, were shown to be effective in restoring iron homeostasis in preliminary studies. Moreover, the natural bioactives astragalus polysaccharide and icariin have been recently recognized as hepcidin expression inductors.

BackgroundCharacteristics of peritoneal membrane is unique and individually different in peritoneal dialysis patients. Relationship between specific nature of peritoneal transport, anemia and inflammation has not yet been extensively studied. We attempted to outline the complex interplay of several biomarkers of iron status and their association with peritoneal transport, degree of inflammation and residual renal function.MethodsA total of 58 patients treated with peritoneal dialysis either CAPD or APD for at least 3 months were enrolled in this study. Full blood count, traditional markers of iron status (transferrin saturation-TSAT and ferritin), serum erythroferrone-ERFE, soluble transferrin receptor (sTfR), hepcidin, zonulin, growth differentiation factor −15 (GDF15), IL-16, hsCRP and hypoxia-inducible factor—α (HIF-1-α; in serum and dialysate) were measured using commercially available tests. We also performed Peritoneal Equilibrium Test and assessed GFR level.ResultsHb levels above 10 g/dL was found in 74% of patients. Hb levels positively correlated with residual renal function and nutritional status. Adequate iron status was diagnosed in 69% of subjects, only in 9% of patients, criteria for absolute iron deficiency were met. Serum ERFE correlated inversely with hepcidin levels but was not associated with erythropoietin stimulating agent dose. Peritoneal transport had strong correlation with dialysate sTfR (p

Erythropoiesis is the predominant consumer of iron in humans and other vertebrates. By decreasing the transcription of the gene encoding the iron-regulatory hormone hepcidin, erythropoietic activity stimulates iron absorption, as well as the release of iron from recycling macrophages and from stores in hepatocytes. The main erythroid regulator of hepcidin is erythroferrone (ERFE), synthesized and secreted by erythroblasts in the marrow and extramedullary sites. The production of ERFE is induced by erythropoietin (EPO) and is also proportional to the total number of responsive erythroblasts. ERFE acts on hepatocytes to suppress the production of hepcidin, through an as yet unknown mechanism that involves the bone morphogenetic protein pathway. By suppressing hepcidin, ERFE facilitates iron delivery during stress erythropoiesis but also contributes to iron overload in anemias with ineffective erythropoiesis. Although most of these mechanisms have been defined in mouse models, studies to date indicate that the pathophysiology of ERFE is similar in humans. ERFE antagonists and mimics may prove useful for the prevention and treatment of iron disorders.

Because of its peculiar redox properties, iron is an essential element in living organisms, being involved in crucial biochemical processes such as oxygen transport, energy production, DNA metabolism, and many others. However, its propensity to accept or donate electrons makes it potentially highly toxic when present in excess and inadequately buffered, as it can generate reactive oxygen species. For this reason, several mechanisms evolved to prevent both iron overload and iron deficiency. At the cellular level, iron regulatory proteins, sensors of intracellular iron levels, and post-transcriptional modifications regulate the expression and translation of genes encoding proteins that modulate the uptake, storage, utilization, and export of iron. At the systemic level, the liver controls body iron levels by producing hepcidin, a peptide hormone that reduces the amount of iron entering the bloodstream by blocking the function of ferroportin, the sole iron exporter in mammals. The regulation of hepcidin occurs through the integration of multiple signals, primarily iron, inflammation and infection, and erythropoiesis. These signals modulate hepcidin levels by accessory proteins such as the hemochromatosis proteins hemojuvelin, HFE, and transferrin receptor 2, the serine protease TMPRSS6, the proinflammatory cytokine IL6, and the erythroid regulator Erythroferrone. The deregulation of the hepcidin/ferroportin axis is the central pathogenic mechanism of diseases characterized by iron overload, such as hemochromatosis and iron-loading anemias, or by iron deficiency, such as IRIDA and anemia of inflammation. Understanding the basic mechanisms involved in the regulation of hepcidin will help in identifying new therapeutic targets to treat these disorders. [ABSTRACT FROM AUTHOR]

Background: Iron overload is a principal reason for morbidity and death in transfusion-dependent beta-thalassemia cases. Erythroferrone hormone (ERFE), a member of tumor necrosis family-alpha (TNF-α) superfamily produced by erythroblasts and stimulated by endogenous or exogenous erythropoietin (EPO), Under these conditions, ERFE inhibits the formation of hepcidin, restoring the functionality of ferro-portin, that is accountable for enhancing intestinal iron absorption and mobilizing iron reserves. Objective: The aim of the currents study is to analyze the role of ERFE in children suffering from beta thalassemia major. Patients and methods: A prospective case-control study was conducted at Tanta University Hospital during the period from March 2021 to November 2021. The study included 40 children previously diagnosed with beta thalassemia major, and 40 healthy children matched in sex and age as a control group. Serum ERFE was calculated utilizing enzyme linked immunosorbent assay (ELISA) technique. Results: Serum ERFE level was significant increase in the beta thalassemia patients' group than control group. In the patients group, serum ERFE was higher in non spleenectomized patients, and in patients receiving blood transfusion more than once/month, also, ERFE was higher in those with serum ferritin >1000 ng/ml. There is significant positive correlation between ERFE level and serum levels of ferritin and transferrin saturation (T.SAT %). Receiver Operating Characteristic (ROC) curve analysis demonstrated that ERFE level above 1.6 ng/ml is the cutoff value indicating iron overload with high diagnostic efficacy. Conclusion: ERFE is a possible diagnostic tool in predicting iron overload with sensitivity 95%, specificity 62 %, and accuracy 78%. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Iron-deficiency anemia (IDA) can be grouped under low hepcidin and high erythroferrone (ERFE) anemia. There is a negative correlation between ERFE and hepcidin, irrespective of the type of anemia. ERFE is a mediator of the response to erythropoietic stress, suppressing hepcidin to promote the mobilization of stored iron and the absorption of dietary iron. OBJECTIVE: The objective was to determine the effect of ERFE hormone on hepcidin level as iron metabolism regulator in patients with iron deficiency (ID). METHODS: The study included 50 female patients with ID who were investigated for complete blood count, serum levels of ferritin, and serum levels of iron using automated hematology, immunology, and chemistry analyzer. ERFE and hepcidin were measured by a specific enzyme-linked immunosorbent assay kit. RESULTS: The serum ERFE levels were higher than normal in all cases and were negatively correlated with serum hepcidin (r = -0.023). In IDA, serum ERFE concentration had a nonsignificant negative correlation with hemoglobin (Hb) concentration. Serum hepcidin concentration had a nonsignificant negative correlation with Hb concentration. Serum ERFE had a nonsignificant negative correlation with Hb% in severe IDA (r = -0.679; P = 0.094) and mild IDA (r = -0.068; P = 0.789). ERFE had a nonsignificant positive correlation with Hb% in moderate IDA (r = 0.069; P = 0.793). Serum hepcidin had a nonsignificant positive correlation with Hb% in severe IDA (r = 0.036; P = 0.939). Serum hepcidin had a nonsignificant negative correlation with Hb% in mild IDA (r = -0.079; P = 0.764) and moderate IDA (r = -0.179; P = 0.491). CONCLUSIONS: The potential of ERFE and hepcidin in diagnosing and categorizing ID disorders is promising. Understanding the mechanism of ERFE/hepcidin interaction will help in developing ERFE-/hepcidin-targeted therapies. [ABSTRACT FROM AUTHOR]

β-Thalassemia is characterized by ineffective erythropoiesis leading to chronic anemia. Thus, increased iron absorption from the duodenum and via blood transfusions is required to maintain normal blood hemoglobin (Hb) levels and iron chelators in the removal of excessive iron. Certain agents are also needed for the improvement of stress erythropoiesis and iron dysregulation. Green tea extract (GTE), which is rich in epigallocatechin-3-gallate (EGCG), is known to possess radical scavenging and iron-chelating activities. We aimed to assess the effects of green tea extract on erythroid regulators, iron mobilization and anti-lipid peroxidation in the liver, spleen, and kidneys of iron-loaded β-globin gene knockout thalassemic (BKO) mice. Our results indicate that treatments of green tea extract and/or deferiprone (DFP) diminished levels of plasma erythropoietin (EPO) and erythroferrone (ERFE), and consistently suppressed kidney Epo and spleen Erfe mRNA expressions (p < .05) in ironloaded BKO mice when compared with untreated mice. Coincidently, the treatments decreased plasma ferritin (Ft) levels, iron content levels in the liver (p < .05), spleen (p < .05), and kidney tissues of iron-loaded BKO mice. Furthermore, lipid-peroxidation products in the tissues and plasma were also decreased when compared with untreated mice. This is the first evidence of the orchestral role of green tea extract abundant with epigallocatechin-3-gallate in improving ineffective erythropoiesis, iron dysregulation and oxidative stress in iron-overloaded β-thalassemic mice. [ABSTRACT FROM AUTHOR]

In recent years, a steady increase in the incidence of inflammatory bowel diseases (IBD) has been observed with anemia as their most common extraintestinal symptom. Erythroferrone and Bone Morphogenetic Protein 6 (BMP-6) are recently identified cytokines involved in the process of increased erythropoiesis in anemia of various pathomechanisms. The aim of this study was to analyze the concentration of erythroferrone and BMP-6 in IBD patients in relation to clinical and laboratory data. The study comprised 148 patients: 118 with IBD, including 73 (61.85%) diagnosed with anemia (42 with Crohn’s disease (CD) (66.7%) and 31 (56.4%) with ulcerative colitis (UC)) and 30 as a control group. The erythroferrone concentration was significantly higher in IBD patients with anemia (p = 0.009) and higher in UC patients both with and without anemia (p = 0.018), compared to the control group. In CD, no similar difference was observed between patients with and without anemia. Regarding BMP-6, higher levels were found in CD patients with anemia compared to the control group (p = 0.021). The positive correlation between BMP-6 and iron concentration in UC was also noticed. In conclusion, we confirm an increase in erythroferrone concentration in the entire group of IBD patients with anemia, while BMP-6 levels were higher only in anemic CD patients. Due to the clinical importance of anemia in IBD, this problem is worth further analysis and research projects.

Erythropoietin (EPO) acts on erythroid progenitor cells to promote their survival and differentiation to mature erythrocytes. Along with this canonical role, EPO is also reported to modulate energy metabolism, resulting in improved glucose tolerance and insulin sensitivity. EPO also stimulates the production of the hormone erythroferrone (ERFE) which acts to suppress hepcidin production, thus increasing dietary iron absorption and mobilizing stored iron for use in erythropoiesis. ERFE (initially termed myonectin) was also reported have an effect on systemic lipid metabolism by promoting the clearance of nonesterifed fatty acids (NEFA) from circulation. As increased levels of circulating NEFA blunt insulin sensitivity and impair glucose tolerance, ERFE-induced clearance of NEFA after EPO administration would have a beneficial effect on glucose metabolism. The aim of this study was to determine if the known metabolic effect of EPO treatment on glucose homeostasis is mediated by ERFE, produced in response to EPO. Mice lacking Erfe did not differ from wild-type mice in blood lipid parameters, blood glucose, and glucose or insulin tolerance at baseline or after chronic EPO treatment. Additionally, hepcidin suppression and the response of erythrocyte parameters to chronic EPO treatment were unaffected by the absence of Erfe. These findings suggest that the known beneficial effects of EPO on glucose metabolism are not attributable to an accompanying increase in ERFE production, and that Erfe is dispensable for normal glucose homeostasis. Furthermore, our data indicate that ERFE-independent mechanisms can suppress hepcidin in response to chronically elevated EPO levels.

The congenital dyserythropoietic anemias are a heterogeneous group of disorders characterized by anemia and ineffective erythropoiesis. Congenital dyserythropoietic anemia type I (CDA1) can present in utero with hydrops fetalis, but more often it presents in childhood or adulthood with moderate macrocytic anemia, jaundice, and progressive iron-overload. CDA1 is inherited in an autosomal recessive manner, with biallelic pathogenic variants in CDAN1 or C15orf41. This case report documents a severe fetal presentation of CDA1 where we identified two novel compound heterozygous mutations in CDAN1 and describes the associated pathologic findings and levels of iron-regulatory proteins hepcidin, erythroferrone, and GDF15.

Ferritin, the central iron storage protein, has attracted attention as a biomarker of severe COVID‐19. Few studies have investigated regulators of iron metabolism in the context of COVID‐19. The aim was to evaluate biomarkers for iron metabolism in the acute phase response to community‐acquired pneumonia (CAP) caused by SARS‐CoV‐2 compared with CAP caused by bacteria or influenza virus in hospitalized patients. A cross‐sectional study of 164 patients from the Surviving Pneumonia Cohort recruited between January 8, 2019 and May 26, 2020. Blood samples were collected at admission and analyzed for levels of C‐reactive protein (CRP), ferritin, soluble transferrin receptor, erythroferrone, and hepcidin. Median (IQR) hepcidin was higher in SARS‐CoV‐2 with 143.8 (100.7–180.7) ng/mL compared with bacterial and influenza infection with 78.8 (40.1–125.4) and 53.5 (25.2–125.8) ng/mL, respectively. The median ferritin level was more than 2‐fold higher in patients with SARS‐CoV‐2 compared with the other etiologies (p < 0.001). Patients with SARS‐CoV‐2 had lower levels of erythroferrone and CRP compared with those infected with bacteria. Higher levels of hepcidin and lower levels of erythroferrone despite lower CRP levels among patients with SARS‐CoV‐2 compared with those infected with bacteria indicate alterations in iron metabolism in patients with SARS‐CoV‐2 infection. [ABSTRACT FROM AUTHOR]

Abstract Background In ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time, the hypothesis that iron overload in megaloblastic anemia may be related to ineffective erythropoiesis is explored by describing the kinetics of hepcidin, erythroferrone, and growth differentiation factor-15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload. Case presentation An 81-year-old Caucasian male was admitted for fatigue. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease. Vitiligo was observed on both hands. Biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation levels. Megaloblastic anemia was confirmed with undetectable blood vitamin B12 and typical cytological findings like hyper-segmented neutrophils in blood and megaloblasts in bone marrow. The patient received vitamin B12 supplementation. At 3 months, biological parameters reached normal values. Hepcidin kinetics from diagnosis to 3 months inversely correlated with those of erythroferrone and growth differentiation factor-15. Conclusions This case suggests that iron-overload mechanisms of dyserythropoietic anemias may apply to megaloblastic anemias.

Abstract Background Decreased erythropoietin levels and impaired iron metabolism due to excessive hepcidin levels are responsible for renal anaemia in patients undergoing haemodialysis. Recently, erythroferrone (ERFE) has been identified as a factor that regulates hepcidin. In addition, fibroblast growth factor 23 (FGF23), which has been recognized as a phosphorus-regulating hormone, appears to be involved in haematopoietic regulation. Clarification of the detailed mechanism of haematopoiesis could lead to the improvement of renal anaemia treatment. Methods Epoetin beta pegol (CERA) was administered to patients undergoing haemodialysis at week 0, and the same amount of CERA with saccharated ferric oxide (SFO) was administered at week 4. The changes in haematopoiesis-related biomarkers, including ERFE, intact FGF23 (iFGF23), C-terminal FGF23 (cFGF23), and inflammatory markers, were examined. Results Administration of CERA increased ERFE levels, decreased hepcidin levels, and stimulated iron usage for haematopoiesis, leading to an increase in reticulocytes (Ret) and haemoglobin (Hb). Simultaneous administration of SFO with CERA (CERA + SFO) significantly attenuated the responses of ERFE, Ret, and Hb compared with CERA alone. Although iFGF23 levels were not affected by either CERA or CERA + SFO, cFGF23 was significantly elevated from baseline after CERA. Since cFGF23 levels were not affected by CERA + SFO, cFGF23 levels after CERA + SFO were significantly lower than those after CERA alone. The ratio of iFGF23 to cFGF23 (i/cFGF23 ratio) was significantly higher after CERA + SFO than that after CERA alone. In addition, high-sensitivity C-reactive protein (hsCRP) levels were significantly higher after CERA + SFO than after CERA alone. Conclusion Administration of SFO suppressed haematopoietic responses induced by CERA. Elevation of i/cFGF23 ratio and hsCRP could account for the inhibitory effects of SFO on haematopoiesis. Trial registration This study was registered with the University Hospital Medical Information Network (ID UMIN000016552 ).

Objective: This study aimed to investigate the effects of hypoxia-inducible factor-1α (HIF-1α), hypoxia-inducible factor-2α (HIF-2α), and erythroferrone (ERFE) on hepcidin in patients with chronic kidney disease (CKD) stages 3–5 and renal anemia. Methods: A total of 90 patients with CKD stages 3–5 and renal anemia were selected for the study at the Nephrology Department of Fujian Provincial People's Hospital and divided into three groups, according to CKD stage, while another 30 healthy subjects who underwent a physical examination at the hospital during the same period were selected as the normal group. The serum levels of hepcidin, HIF-1α, HIF-2α, ERFE, and furin were measured using an avidin biotin peroxidase complex enzyme-linked immunosorbent assay to compare the differences between the groups in the related indicators. Results: ① Serum HIF-2α, HIF-1α, ERFE, and furin levels increased gradually in the patients with CKD stages 3–5 (p < 0.05, p < 0.01). ②Simple correlation analysis:Serum hepcidin was positively correlated with HIF-2α, ERFE, and HIF-1α in the CKD patients (p < 0.01). ③Serum hepcidin was positively correlated with HIF-2α, HIF-1α, and ERFE in the CKD patients injected with erythropoietin (EPO) (p < 0.01), while serum hepcidin was positively correlated with HIF-2α and HIF-1α (p < 0.01) in the patients not injected with EPO. ④ Multivariate linear regression analysis showed that HIF-1α, (β = 4.36, p < 0.01), serum ferritin(SF) (β = 0.13, p < 0.01), and HIF-2α (β = 0.66, p < 0.01) were significantly correlated with hepcidin. Conclusion: HIF-1α, HIF-2α, and SF are factors which have an effect on hepcidin in patients with CKD stages 3–5 and renal anemia. The increase of HIF-1α, HIF-2α, and ERFE does not seem to inhibit the increase of hepcidin. [ABSTRACT FROM AUTHOR]

Iron is necessary for essential processes in every cell of the body, but the erythropoietic compartment is a privileged iron consumer. In fact, as a necessary component of hemoglobin and myoglobin, iron assures oxygen distribution; therefore, a considerable amount of iron is required daily for hemoglobin synthesis and erythroid cell proliferation. Therefore, a tight link exists between iron metabolism and erythropoiesis. The liver-derived hormone hepcidin, which controls iron homeostasis via its interaction with the iron exporter ferroportin, coordinates erythropoietic activity and iron homeostasis. When erythropoiesis is enhanced, iron availability to the erythron is mainly ensured by inhibiting hepcidin expression, thereby increasing ferroportin-mediated iron export from both duodenal absorptive cells and reticuloendothelial cells that process old and/or damaged red blood cells. Erythroferrone, a factor produced and secreted by erythroid precursors in response to erythropoietin, has been identified and characterized as a suppressor of hepcidin synthesis to allow iron mobilization and facilitate erythropoiesis. [ABSTRACT FROM AUTHOR]

Erythropoietic response is controlled not only by erythropoietin but also by iron. In addition to its role in iron delivery, transferrin also functions as a signaling molecule, with effects on both iron homeostasis and erythropoiesis. We investigated hematologic parameters, iron status and expression of key proteins, including the hepatic iron regulatory protein hepcidin and the suppressive erythroid factor Erfe , in mice subject to dietary iron deficiency with and without anemia. The acute effect of iron on these parameters was investigated by administration of exogenous iron-loaded transferrin (holoTf) in each of the mouse models. Serum iron in mice with iron deficiency (ID) is modestly lower with hematologic parameters maintained by utilization of iron stores in mice with ID. As expected, erythropoietin expression and concentration, along with marrow Erfe are unaffected in ID mice. Administration of holoTf restores serum iron and Tf saturation levels to those observed in control mice and results in an increase in hepcidin compared to ID mice not treated with holoTf. The expression of the Bmp signaling molecule Bmp6 is not significantly increased following Tf treatment in ID mice. Thus, the expression level of the gene encoding hepcidin, Hamp1 , is increased relative to Bmp6 expression in ID mice following treatment with holoTf, leading us to speculate that Tf saturation may influence Bmp sensitivity. In mice with iron deficiency anemia (IDA), decreased hematologic parameters were accompanied by pronounced decreases in serum and tissue iron concentrations, and an increase in serum erythropoietin. In the absence of exogenous holoTf, the greater serum erythropoietin was not reflected by an increase in marrow Erfe expression. HoloTf administration did not acutely change serum Epo in IDA mice. Marrow Erfe expression was, however, markedly increased in IDA mice following holoTf, plausibly accounting for the lack of an increase in Hamp1 following holoTf treatment in the IDA mice. The increase in Erfe despite no change in erythropoietin suggests that Tf acts to increase erythropoietin sensitivity. These observations underscore the importance of Tf in modulating the erythropoietic response in recovery from iron deficiency anemia, with implications for other stress erythropoiesis conditions. [ABSTRACT FROM AUTHOR]

Erythroferrone is a recently identified erythroid regulator produced by erythroblasts in the mammalian bone marrow and extramedullary sites, known to be induced in conditions of anemia or blood loss. Iron metabolism is affected by erythroferrone through its capacity to inhibit hepcidin production, leading to the increase of iron availability required for erythropoiesis. However, little is known about erythroferrone function in other vertebrates, in particular teleost fish, that unlike mammals, present two different functional types of hepcidin, one type mostly involved in iron metabolism and the other in antimicrobial response. The study of erythroferrone evolution and its biological role in teleost fish can give us valuably new insights into its function. To address these questions, we characterized erythroferrone in the European sea bass (Dicentrarchus labrax), a species presenting two hepcidin types, and evaluated variations in its expression levels in response to different experimental conditions. During experimental anemia, erythroferrone responds by increasing its expression and suppressing hepcidin production, following the pattern observed in mammals, but it is not influenced by iron overload. However, during bacterial infection, erythroferrone is downregulated and hepcidin levels increase. Furthermore, administration of Hamp1 but not of Hamp2 peptides suppresses erythroferrone expression. In conclusion, in dual hepcidin teleost fish erythroferrone seems to only interact with type 1 hepcidin, known to be involved in iron homeostasis, but not with type 2, which has an almost exclusive antimicrobial role. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) affects 8% to 16% of the global population and is characterized as a persistent impairment in kidney structure or function (e.g., glomerular filtration rate [GFR] 60 mL/min/1.73 m2 or albuminuria 30 mg per 24 hours) for more than 3 months. Anemia is a prevalent complication in chronic kidney disease (CKD) patients, especially those on hemodialysis for end-stage renal disease (ESRD). In CKD patients, erythropoietin deficiency is the most common cause of anemia. The erythropoietin stimulating agent (ESA) is the most common therapy for anemia in people with chronic kidney disease. In CKD patients using ESAs, the clinical practice guidelines Kidney Disease: Improving Global Outcomes (KDIGO) 2012 suggested that hemoglobin levels be kept between 11 and 12 g/dL. Despite proper ESA medication, some patients remain anemic or lose ESA response over time, a condition known as ESA hypo-responsiveness. The liver transmembrane serine protease matriptase-2 (MT2) has been discovered to have a key function in regulating hepcidin gene expression. High hepcidin expression and severe microcytic anemia are caused by mutations in the TMPRSS6 gene, which codes for matriptase-2. As a result, matriptase-2 is vital for iron homeostasis and may play a role in ESRD. Erythroferrone (ERFE) is a glycoprotein hormone produced by erythroblasts and released by them. Recently discovered to be an erythropoietic regulator that is activated in response to erythropoietin stimulation (Epo). By suppressing hepcidin and excess absorption with iron mobilization, it controlled iron metabolism. Anemia is a characteristic illness in chronic kidney disease (CKD) due to a decline in hyposensitive erythropoietic to the Epo; these patients are advised to utilize erythropoiesis-stimulating medications (ESAs). Study design: comparative cross sectional study. These studies include 90 participants (60 patients kept on hemodialysis with oral or intravenous iron and ESA therapy, 30 patients of which responsive to treatment (Hb > 11 g/dl) and the 30 patients remaining hypo responsive to treatment (Hb < 11 g/dl), (30 patients kept on hemodialysis without iron and ESA therapy) the age range (46-73) years. The following biochemical parameters have been studied, Matriptase2 and Erythroferrone by ELISA method, urea, creatinine, electrolyte (Na, K, Ca, PO4), iron, ferritin and TIBC by enzymatic method, Hb was measured, TSAT(%) = serum iron/TIBC ×100, also, Body mass index (BMI), duration of CKD, frequency of CKD and causes of CKD was reported. The patients groups with responsive to ESA and iron therapy showed a significant elevation in serum levels of MT2 and ERFE in comparison with hypo-responsive group and without ESA and iron therapy group (p<0.001). As well as, there is a significant increase in serum levels of MT2 in patients groups without ESA and iron therapy in comparison with hypo-responsive group (p=0.02). In conclusion, a high level of serum matriptase 2 and erythroferrone were found in patients with chronic kidney disease under hemdialysis how responsive to erythropoiesis stimulating agents and iron therapy. This incidence may be used as a prognostic indicator to determine the level of response to treatment. [ABSTRACT FROM AUTHOR]

Erythroferrone is a recently identified erythroid regulator produced by erythroblasts in the mammalian bone marrow and extramedullary sites, known to be induced in conditions of anemia or blood loss. Iron metabolism is affected by erythroferrone through its capacity to inhibit hepcidin production, leading to the increase of iron availability required for erythropoiesis. However, little is known about erythroferrone function in other vertebrates, in particular teleost fish, that unlike mammals, present two different functional types of hepcidin, one type mostly involved in iron metabolism and the other in antimicrobial response. The study of erythroferrone evolution and its biological role in teleost fish can give us valuably new insights into its function. To address these questions, we characterized erythroferrone in the European sea bass (Dicentrarchus labrax), a species presenting two hepcidin types, and evaluated variations in its expression levels in response to different experimental conditions. During experimental anemia, erythroferrone responds by increasing its expression and suppressing hepcidin production, following the pattern observed in mammals, but it is not influenced by iron overload. However, during bacterial infection, erythroferrone is downregulated and hepcidin levels increase. Furthermore, administration of Hamp1 but not of Hamp2 peptides suppresses erythroferrone expression. In conclusion, in dual hepcidin teleost fish erythroferrone seems to only interact with type 1 hepcidin, known to be involved in iron homeostasis, but not with type 2, which has an almost exclusive antimicrobial role.

Background:Thalassemia is an inherited blood disorder of the blood cells It is described as a low level of hemoglobin and a decrease in the number of red blood cells from the normal range. Objective: This study amied to evaluate the levels and find the correlation coefficient between erythroferrone and liver enzymes in the beta thalassemia patients. Patients and Methods: In this study, samples were taken from patients with beta-thalassemia (60 samples) and 30 samples from healthy people. Results: The current study's findings demonstrated that both erythroferon and liver enzymes were highly elevated in patients with thalassemia (P>0.05), and they were also strongly associated. Conclusions: This study found association between increased levels of erythroferon and severe anemia also association between increased levels of liver enzymes and severe accumulation of iron. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the effects of hypoxia-inducible factor-1α (HIF-1α), hypoxia-inducible factor-2α (HIF-2α), and erythroferrone (ERFE) on hepcidin in patients with chronic kidney disease (CKD) stages 3-5 and renal anemia. Methods: A total of 90 patients with CKD stages 3-5 and renal anemia were selected for the study at the Nephrology Department of Fujian Provincial People's Hospital and divided into three groups, according to CKD stage, while another 30 healthy subjects who underwent a physical examination at the hospital during the same period were selected as the normal group. The serum levels of hepcidin, HIF-1α, HIF-2α, ERFE, and furin were measured using an avidin biotin peroxidase complex enzyme-linked immunosorbent assay to compare the differences between the groups in the related indicators. Results: 1Serum HIF-2α, HIF-1α, ERFE, and furin levels increased gradually in the patients with CKD stages 3-5 (p < 0.05, p < 0.01). 2Simple correlation analysis:Serum hepcidin was positively correlated with HIF-2α, ERFE, and HIF-1α in the CKD patients (p < 0.01). 3Serum hepcidin was positively correlated with HIF-2α, HIF-1α, and ERFE in the CKD patients injected with erythropoietin (EPO) (p < 0.01), while serum hepcidin was positively correlated with HIF-2α and HIF-1α (p < 0.01) in the patients not injected with EPO. 4 Multivariate linear regression analysis showed that HIF-1α, (β = 4.36, p < 0.01), serum ferritin(SF) (β = 0.13, p < 0.01), and HIF-2α (β = 0.66, p < 0.01) were significantly correlated with hepcidin. Conclusion: HIF-1α, HIF-2α, and SF are factors which have an effect on hepcidin in patients with CKD stages 3-5 and renal anemia. The increase of HIF-1α, HIF-2α, and ERFE does not seem to inhibit the increase of hepcidin. [ABSTRACT FROM AUTHOR]

Background: Anemia-associated chronic kidney disease increases in more advanced stages with a subsequent acceleration in renal impairment progressing to end-stage renal disease. Although hepcidin and erythroferrone have been described as novel biomarkers of iron metabolism, there is still an area of ambiguity regarding iron utility in anemia-associated end-stage renal disease., Objectives: This study aims to determine the correlations between erythropoietin, erythroferrone, and hepcidin-25 in hemodialysis, and to evaluate the clinical utility of the hepcidin-25/erythroferrone ratio as a biomarker of erythropoiesis-stimulating agent effectiveness compared to reticulocyte maturation parameters., Methods: Serum erythropoietin, erythroferrone, and hepcidin-25 levels in 35 dialysis-dependent patients on a maintenance dose of a short-acting erythropoiesis-stimulating agent were consequently assessed on Days 0, 5, and 7. The erythropoiesis activity was monitored by measuring the increment in reticulocyte maturation parameters., Results: Though the effectiveness of erythropoiesis in these patients was not associated with the hepcidin-25/erythroferrone ratio, it was lower among those with effective erythropoiesis than those with ineffective erythropoiesis. The effective group showed a statistically significant increase in reticulocyte maturation parameters compared to the ineffective group., Conclusions: The findings show the pathogenesis of iron homeostasis in hemodialysis, the validity of hepcidin-25/erythroferrone ratio as a biomarker of erythropoiesis-stimulating agent effectiveness, and the advantageous monitoring of reticulocyte maturation measures to improve management of anemia-associated chronic kidney disease., Competing Interests: Conflicts of interest All authors declare that they have no conflict of interest., (Copyright © 2024 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier España, S.L.U. All rights reserved.)

Beyond its core role in iron metabolism, erythroferrone (ERFE) has emerged as a key player with far-reaching implications in various hematologic disorders. Its regulatory effect on hepcidin underlines its significance in conditions characterized by disrupted iron homeostasis. In β-thalassemia and myelodysplastic syndromes, its dysregulation intricately contributes to the clinical challenges of anemia and iron overload which highlights its potential as a therapeutic target. In anemia of chronic disease and iron deficiency anemia, ERFE presents a unique profile. In chronic kidney disease (CKD), the intricate interplay between ERFE, erythropoietin, and hepcidin undergoes dysregulation, contributing to the complex iron imbalance characteristic of this condition. Recent research suggests that ERFE plays a multifaceted role in restoring iron balance in CKD, beyond simply suppressing hepcidin production. The potential to modulate ERFE activity offers a novel approach to treating a spectrum of disorders associated with iron dysregulation. As our understanding of ERFE continues to evolve, it is poised to become a key focus in the development of targeted treatments, making it an exciting and dynamic area of ongoing research. Modulating ERFE activity presents a groundbreaking approach to treat iron dysregulation in conditions like iron deficiency anemia, thalassemia, and hemochromatosis. As new research unveils its intricate roles, ERFE has rapidly emerged as a key target for developing targeted therapies like ERFE agonists and antagonists. With promising studies underway, this dynamic field holds immense potential to improve patient outcomes, reduce complications, and offer personalized treatment options in hematology research. This comprehensive overview of ERFE's role across various conditions underscores its pivotal function in iron metabolism and associated pathologies., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the Chinese Medical Association (CMA) and Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College (IHCAMS).)

Background: In ineffective erythropoiesis, hepcidin synthesis is suppressed by erythroid regulators, namely erythroferrone and growth differentiation factor-15. For the first time, the hypothesis that iron overload in megaloblastic anemia may be related to ineffective erythropoiesis is explored by describing the kinetics of hepcidin, erythroferrone, and growth differentiation factor-15 levels in a patient diagnosed with megaloblastic anemia associated with iron overload.Case Presentation: An 81-year-old Caucasian male was admitted for fatigue. He had type-2 diabetes previously treated with metformin, ischemic cardiac insufficiency, and stage-3 chronic kidney disease. Vitiligo was observed on both hands. Biological tests revealed normocytic non-regenerative anemia associated with hemolysis, thrombocytopenia, and elevated sideremia, ferritin, and transferrin saturation levels. Megaloblastic anemia was confirmed with undetectable blood vitamin B12 and typical cytological findings like hyper-segmented neutrophils in blood and megaloblasts in bone marrow. The patient received vitamin B12 supplementation. At 3 months, biological parameters reached normal values. Hepcidin kinetics from diagnosis to 3 months inversely correlated with those of erythroferrone and growth differentiation factor-15.Conclusions: This case suggests that iron-overload mechanisms of dyserythropoietic anemias may apply to megaloblastic anemias. [ABSTRACT FROM AUTHOR]

Purpose: Erythroferrone (ERFE) is well acknowledged for its inhibitory function on hepcidin synthesis in the liver during stress erythropoiesis, thereby ensuring sufficient iron supply to bone marrow erythroblasts. Hepcidin plays an indispensable role in the pathogenesis of anemia of chronic disease (ACD). Thus, ERFE was suggested to protect against ACD in various diseases. Rheumatoid arthritis (RA) is commonly involved with ACD and high hepcidin levels, with a further increase of the latter in active states. The present study is a case-control study that aimed to determine the pattern of ERFE expression in RA patients with concomitant ACD and study its relationship with hepcidin, erythropoietin (EPO) and disease activity. Patients and Methods: Fifty-five RA patients with ACD were categorized into active and inactive RA using the disease activity score (DAS28); 15 healthy subjects were included as control subjects. ERFE was measured for patients and control subjects using quantitative real-time polymerase chain reaction, in addition to testing for CBC, ESR, CRP, iron profile parameters and hepcidin. EPO was assessed for patients of both active and inactive RA groups. Results: ERFE and hepcidin showed the highest levels in active RA; ERFE values were similar in control subjects and inactive RA patients, while hepcidin was significantly higher in inactive RA than control subjects. Patients with high ERFE levels had higher RBC, Hct, MCV, hepcidin and EPO levels. Stepwise regression analysis has identified DAS28 and disease duration as the best predictors of ERFE values, whereas ERFE and hepcidin were independent predictors of disease activity. Conclusion: We introduce ERFE as a novel marker of RA activity. Although the inhibitory effect of ERFE on hepcidin is not evident, our results still indicate that ERFE may have a beneficial erythropoietic effect in the context of ACD in RA disease activity. [ABSTRACT FROM AUTHOR]

Purpose of reviewIron homeostasis and erythropoiesis regulate each other to ensure optimal delivery of oxygen and iron to cells and tissues. Defining the mechanisms of this crosstalk is important for understanding the pathogenesis of common conditions associated with disordered iron metabolism and erythropoiesis.Recent findingsStress erythropoiesis causes suppression of hepcidin to increase iron availability for hemoglobin synthesis. The erythroid hormone erythroferrone (ERFE) was identified as the mediator of this process. ERFE and additional candidates (TWSG1 and GDF15) may also mediate hepcidin suppression in ineffective erythropoiesis. Several mechanisms by which iron regulates erythropoiesis were also recently identified. Iron deficiency suppresses erythropoietin production via the IRP1-HIF2α axis to prevent excessive iron usage by erythropoiesis during systemic iron restriction. Iron restriction also directly impairs erythroid maturation by inhibiting aconitase, and this can be reversed by the administration of the aconitase product isocitrate. Another novel target is GDF11, which is thought to autoinhibit erythroid maturation. GDF11 traps show promising pharmacologic activity in models of both ineffective erythropoiesis and iron-restricted anemia.SummaryThis review summarizes exciting advances in understanding the mechanisms of iron and erythropoietic regulation, and development of novel therapeutic tools for disorders resulting from dysregulation of iron metabolism or erythropoiesis.

Background: Erythroblast erythroferrone (ERFE) secretion inhibits hepcidin expression by sequestering several bone morphogenetic protein (BMP) family members to increase iron availability for erythropoiesis. Methods: To address whether ERFE functions also in bone and whether the mechanism of ERFE action in bone involves BMPs, we utilize the Erfe-/- mouse model as well as β–thalassemic (Hbbth3/+) mice with systemic loss of ERFE expression. In additional, we employ comprehensive skeletal phenotyping analyses as well as functional assays in vitro to address mechanistically the function of ERFE in bone. Results: We report that ERFE expression in osteoblasts is higher compared with erythroblasts, is independent of erythropoietin, and functional in suppressing hepatocyte hepcidin expression. Erfe-/- mice display low–bone–mass arising from increased bone resorption despite a concomitant increase in bone formation. Consistently, Erfe-/- osteoblasts exhibit enhanced mineralization, Sost and Rankl expression, and BMP–mediated signaling ex vivo. The ERFE effect on osteoclasts is mediated through increased osteoblastic RANKL and sclerostin expression, increasing osteoclastogenesis in Erfe-/- mice. Importantly, Erfe loss in Hbbth3/+mice, a disease model with increased ERFE expression, triggers profound osteoclastic bone resorption and bone loss. Conclusions: Together, ERFE exerts an osteoprotective effect by modulating BMP signaling in osteoblasts, decreasing RANKL production to limit osteoclastogenesis, and prevents excessive bone loss during expanded erythropoiesis in β–thalassemia. Funding: YZG acknowledges the support of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (R01 DK107670 to YZG and DK095112 to RF, SR, and YZG). MZ acknowledges the support of the National Institute on Aging (U19 AG60917) and NIDDK (R01 DK113627). TY acknowledges the support of the National Institute on Aging (R01 AG71870). SR acknowledges the support of NIDDK (R01 DK090554) and Commonwealth Universal Research Enhancement (CURE) Program Pennsylvania.