Regulator Of Iron Homeostasis Research Articles

Twenty years after its discovery, hepcidin is still considered the main regulator of iron homeostasis in humans. The increase in hepcidin expression drastically blocks the flow of iron, which can come from one's diet, from iron stores, and from erythrophagocytosis. Many anemic conditions are caused by non-physiologic increases in hepcidin. The sequestration of iron in the intestine and in other tissues poses worrying premises in view of discoveries about the mechanisms of ferroptosis. The nutritional treatment of these anemic states cannot ignore the nutritional modulation of hepcidin, in addition to the bioavailability of iron. This work aims to describe and summarize the few findings about the role of hepcidin in anemic diseases and ferroptosis, as well as the modulation of hepcidin levels by diet and nutrients.

Iron overload and ferroptosis are associated with intervertebral disc degeneration (IDD); however, the mechanism underlying the regulation of iron homeostasis remains to be elucidated. Nuclear factor erythroid 2‑related factor 2 (Nrf2) has been reported to regulate cellular iron homeostasis; however, its impact on IDD pathology and the underlying mechanism of action requires further investigation. In the present study, immunohistochemistry analysis of Nrf2 expression in the cartilage endplate (CEP) was conducted and it was demonstrated that Nrf2 expression was increased in the CEP at the early stages of the development of IDD, whereas it was decreased at the late stages of the development of IDD. The results of western blot analysis indicated that the inadequate activation of Nrf2 may aggravate mitochondrial dysfunction and oxidative stress, thus promoting CEP chondrocyte degeneration and calcification. It was also revealed that Nrf2 was involved in TNF‑α‑induced CEP chondrocyte iron metabolism dysfunction and ferroptosis. Inhibition of Nrf2 expression using Nrf2 small interfering RNA could enhance the process of nuclear receptor coactivator 4 (NCOA4)‑mediated ferritinophagy and increase ferrous ion content, which may promote CEP chondrocyte ferroptotic cell death and extracellular matrix degradation. Furthermore, a decrease in cellular iron concentration may inhibit CEP chondrocyte ferroptosis, and CEP degeneration and calcification. The present study highlights the role of the Nrf2/NCOA4 axis in chondrocyte ferroptosis and IDD pathogenesis, thus suggesting that activation of Nrf2 may be a promising strategy for IDD treatment.

Glycine recalibrates iron homeostasis of lens epithelial cells by blocking lysosome-dependent ferritin degradation

Single Ascending Doses of REGN7999, a Monoclonal Antibody Inhibitor of TMPRSS6, Increase Serum Hepcidin and Cause Deep, Sustained Reductions in Serum Iron in Healthy Human Volunteers

Novel Anti-TMPRSS6 Monoclonal Antibody Provides a Potential Therapeutic Approach for the Treatment of Polycythemia Vera

Alphafold2-Assisted Structure-Function Analysis of Human Erythroferrone Relevant for Its Iron-Regulatory Function

Maintaining theintracellular iron concentration within the homeostatic range is vital to meet cellular metabolic needs and reduce oxidative stress. Previous research revealed that the haloarchaeon Halobacterium salinarum encodes four diphtheria toxin repressor (DtxR) family transcription factors (TFs) that together regulate the iron response through an interconnected transcriptional regulatory network (TRN). However, the conservation of the TRN andthe metal specificity of DtxR TFsremained poorly understood. Here we identified and characterized the TRN of Haloferax volcanii for comparison. Genetic analysis demonstrated that Hfx. volcanii relies on three DtxR transcriptional regulators (Idr, SirR, and TroR), with TroR as the primary regulator of iron homeostasis. Bioinformatics and molecular approaches revealed that TroR binds a conserved cis-regulatory motif located ∼100 nt upstream of the start codon of iron-related target genes. Transcriptomics analysis demonstrated that, under conditions of iron sufficiency, TroR repressed iron uptake and induced iron storage mechanisms. TroR repressed the expression of one other DtxR TF, Idr. This reduced DtxR TRN complexity relative to that of Hbt. salinarum appeared correlated with natural variations in iron availability. Based on these data, we hypothesize that variable environmental conditions such as iron availability appear to select forincreasing TRN complexity.

Malaria remains a significant global health threat, causing hundreds of thousands of deaths annually. Understanding the host's protective mechanisms against this parasitic infection is crucial for developing effective prevention and treatment strategies. Hepcidin, a central regulator of iron homeostasis, has emerged as a key player in the host's defense against malaria. This comprehensive review explores the multifaceted roles of hepcidin in safeguarding the host from malaria infection. We delve into the molecular mechanisms of hepcidin regulation and its impact on the intricate interplay between iron, the immune system, and Plasmodium species. Additionally, we discuss the potential therapeutic implications of targeting hepcidin to enhance antimalarial responses. By shedding light on hepcidin's antimalarial arsenal, this review aims to contribute to the development of innovative strategies for combating malaria. Keywords: Hepcidin, antimalaria, malaria and host

Spinal cord injury (SCI) can lead to iron overloading and subsequent neuronal ferroptosis, which hinders the recovery of locomotor function. However, it is still unclear whether the maintenance of neuronal iron homeostasis enables to revitalize intrinsic neurogenesis. Herein, we report the regulation of cellular iron homeostasis after SCI via the chelation of excess iron ions and modulation of the iron transportation pathway using polyphenol-based hydrogels for the revitalization of intrinsic neurogenesis. The reversed iron overloading can promote neural stem/progenitor cell differentiation into neurons and elicit the regenerative potential of newborn neurons, which is accompanied by improved axon reinnervation and remyelination. Notably, polyphenol-based hydrogels significantly increase the neurological motor scores from ~8 to 18 (out of 21) and restore the transmission of sensory and motor electrophysiological signals after SCI. Maintenance of iron homeostasis at the site of SCI using polyphenol-based hydrogels provides a promising paradigm to revitalize neurogenesis for the treatment of iron accumulation-related nervous system diseases.

Background. Ferritin is an important integral and diagnostic marker of liver diseases. In 1/3 of patients with nonalcoholic fatty liver disease (NAFLD), manifestations of hyperferritinemia are revealed. Increased ferritin level indicates the severity of the disease course and affects the prognosis.Objective: to determine the prevalence and character of hyperferritinemia manifestations in NAFLD patients and to evaluate the effectiveness of its correction with human placenta hydrolysate.Material and methods. We examined 158 patients aged from 20 to 63 years (92 men and 66 women). There were no significant differences in age between men and women. The control group consisted of 20 practically healthy individuals. Molecular mechanisms of peptide components of human placenta hydrolysate (Laennec®) impact on pathophysiological processes of serum ferritin disorders, iron metabolism indicators, and inflammation manifestations were analyzed.Results. Nineteen peptides potentially important for regulation of iron homeostasis were identified in Laennec® composition. These peptides contribute to the elimination of iron metabolism disorders by regulating the levels of hepcidin (the main hormone of iron homeostasis), reducing ferritin synthesis, as well as exhibiting anti-inflammatory, and immunomodulatory effects. The efficacy of the drug monotherapy in patients with hyperferritinemia was shown.Conclusion. Laennec® was found to be one of the medicines contributing to the reduction of hyperferritinemia manifestations, iron metabolism disorders, and systemic inflammatory process in NAFLD.

Abstract JOURNAL/nrgr/04.03/01300535-202407000-00037/figure1/v/2023-11-20T171125Z/r/image-tiff Interfering with the ferroptosis pathway is a new strategy for the treatment of spinal cord injury. Fibroblast growth factor 21 can inhibit ferroptosis and promote neurofunctional recovery, while heme oxygenase-1 is a regulator of iron and reactive oxygen species homeostasis. The relationship between heme oxygenase-1 and ferroptosis remains controversial. In this study, we used a spinal cord injury rat model to show that the levels of fibroblast growth factor 21 in spinal cord tissue decreased after spinal cord injury. In addition, there was a significant aggravation of ferroptosis and a rapid increase in heme oxygenase-1 expression after spinal cord injury. Further, heme oxygenase-1 aggravated ferroptosis after spinal cord injury, while fibroblast growth factor 21 inhibited ferroptosis by downregulating heme oxygenase-1. Thus, the activation of fibroblast growth factor 21 may provide a potential treatment for spinal cord injury. These findings could provide a new potential mechanistic explanation for fibroblast growth factor 21 in the treatment of spinal cord injury.

The Bol2 homolog Fra2 and monothiol glutaredoxin Grx4 together play essential roles in regulating iron homeostasis in Schizosaccharomyces pombe. In vivo studies indicate that Grx4 and Fra2 act as co-inhibitory partners that inactivate the transcriptional repressor Fep1 in response to iron deficiency. In Saccharomyces cerevisiae, Bol2 is known to form a [2Fe-2S]-bridged heterodimer with the monothiol glutaredoxins Grx3 and Grx4, with the cluster ligands provided by conserved residues in Grx3/4 and Bol2 as well as glutathione (GSH). In this study, we characterized this analogous [2Fe-2S]-bridged Grx4-Fra2 complex in S. pombe by identifying the specific residues in Fra2 that act as ligands for the Fe-S cluster and are required to regulate Fep1 activity. We present spectroscopic and biochemical evidence confirming the formation of a [2Fe-2S]-bridged Grx4-Fra2 heterodimer with His66 and Cys29 from Fra2 serving as Fe-S cluster ligands in S. pombe. In vivo transcription and growth assays confirm that both His66 and Cys29 are required to fully mediate the response of Fep1 to low iron conditions. Furthermore, we analyzed the interaction between Fep1 and Grx4-Fra2 using circular dichroism spectroscopy to monitor changes in Fe-S cluster coordination chemistry. These experiments demonstrate unidirectional [2Fe-2S] cluster transfer from Fep1 to Grx4-Fra2 in the presence of GSH, revealing the Fe-S cluster dependent mechanism of Fep1 inactivation mediated by Grx4 and Fra2 in response to iron deficiency.

Hepcidin from Onychostoma macrolepis: Response to Aeromonas hydrophila infection by down-regulating expression of inflammatory factor genes and regulating iron homeostasis potentially

Estrogens and Prolactin Do Not Regulate Maternal and Embryo Iron Homeostasis during Pregnancy

A Phase 1b Double-Blind, Placebo-Controlled Study of DISC-0974, an Anti-Hemojuvelin Antibody, in Patients with Non-Dialysis Dependent Chronic Kidney Disease and Anemia

A Phase 1b Trial of DISC-0974, an Anti-Hemojuvelin Antibody, in Patients with Myelofibrosis and Anemia

ALK2 and JAK2 Inhibition for Improved Treatment of Anemia in Myelofibrosis Patients: Preclinical Profile of an ALK2 Inhibitor Zilurgisertib in Combination with Ruxolitinib

Capsaicin (CAP), a frequently occurring alkaloid component found in spicy peppers, has demonstrated therapeutic potential against tumors, metabolic disease, and cardiovascular disorders. Doxorubicin (DOX), a widely used anthracycline drug in chemotherapy, is notorious for its cardiotoxicity. This study aimed to investigate the potential of CAP in mitigating DOX toxicity in mouse hearts and H9C2 cells, as well as to explore the underlying mechanisms. In our study, we conducted experiments on both mice and H9C2 cells. The mice were divided into four groups and treated with different substances: normal saline, CAP, DOX and CAP+DOX. We evaluated the induction of ferroptosis by DOX and the remission of ferroptosis by CAP using various methods, including echocardiography, Hematoxylin and Eosin (H&E) staining, Masson's trichrome staining, and determination of ferroptosis metabolites, genes and proteins. Additionally, we employed RNA-seq to identify the inhibitory effect of CAP on DOX-induced myocardial apoptosis, which was further confirmed through western blotting. Similar approaches were applied to H9C2 cells, yielding reliable results. Our study demonstrated that treatment with CAP improved the survival rate of DOX-treated mice and reduced myocardial injury. Mechanistically, CAP downregulated transferrin (Trf) and upregulated solute carrier family 40 member 1 (SLC40A1), which helped maintain iron levels in the cells and prevent ferroptosis. Furthermore, CAP inhibited DOX-induced apoptosis by modulating the phosphoinositide 3-kinase (PI3K)- protein kinase B (Akt) signaling pathway. Specifically, CAP activated the PI3K-Akt pathway and regulated downstream BCL2 and BAX to mitigate DOX-induced apoptosis. Therefore, our results suggest that CAP effectively alleviates acute myocardial injury induced by DOX. Our findings demonstrate that CAP has the potential to alleviate DOX-induced ferroptosis by regulating iron homeostasis. Additionally, it can inhibit DOX-induced apoptosis by activating PI3K-Akt signaling pathway.

Ferroptosis is a form of programmed cell death driven by iron-dependent lipid peroxidation (LPO) with the potential for antitumor immunity activation. In this study, a nonferrous cyclopentadienyl metal-based ferroptosis inducer [Ir(Cp*)(Bet)Cl]Cl (Ir-Bet) was developed by a metal-ligand synergistic enhancement (MLSE) strategy involving the reaction of [Ir(Cp*)Cl]2 Cl2 with the natural product Betulin. The fusion of Betulin with iridium cyclopentadienyl (Ir-Cp*) species as Ir-Bet not only tremendously enhanced the antiproliferative activity toward cancer cells, but also activated ferritinophagy for iron homeostasis regulation by PI3K/Akt/mTOR cascade inhibition with a lower dosage of Betulin, and then evoked an immune response by nuclear factor kappa-B (NF-κB) activation of Ir-Cp* species. Further immunogenic cell death (ICD) occurred by remarkable ferroptosis through glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) deactivation and ferritinophagy. An in vivo vaccination experiment demonstrated desirable antitumor and immunogenic effects of Ir-Bet by increasing the ratio of cytotoxic T cells (CTLs)/regulatory T cells (Tregs).

Abstract Ferroptosis is a form of programmed cell death driven by iron‐dependent lipid peroxidation (LPO) with the potential for antitumor immunity activation. In this study, a nonferrous cyclopentadienyl metal‐based ferroptosis inducer [Ir(Cp*)(Bet)Cl]Cl (Ir‐Bet) was developed by a metal‐ligand synergistic enhancement (MLSE) strategy involving the reaction of [Ir(Cp*)Cl]2Cl2 with the natural product Betulin. The fusion of Betulin with iridium cyclopentadienyl (Ir‐Cp*) species as Ir‐Bet not only tremendously enhanced the antiproliferative activity toward cancer cells, but also activated ferritinophagy for iron homeostasis regulation by PI3K/Akt/mTOR cascade inhibition with a lower dosage of Betulin, and then evoked an immune response by nuclear factor kappa‐B (NF‐κB) activation of Ir‐Cp* species. Further immunogenic cell death (ICD) occurred by remarkable ferroptosis through glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) deactivation and ferritinophagy. An in vivo vaccination experiment demonstrated desirable antitumor and immunogenic effects of Ir‐Bet by increasing the ratio of cytotoxic T cells (CTLs)/regulatory T cells (Tregs).