Iron homeostasis is critical for multiple physiological and pathological processes. DMT1, a core iron transporter, is expressed in almost all cells and organs and altered in response to various conditions, whereas, there is few reviews focusing on DMT1 in diseases associated with aberrant iron metabolism. Based on available knowledge, this review described a full view of DMT1 and summarized the roles of DMT1 and DMT1-mediated iron metabolism in the onset and development of inflammatory and degenerative diseases. This review also provided an overview of DMT1-related treatment in these disorders, highlighting its therapeutic potential in chronic inflammatory and degenerative diseases.

Iron dysregulation has emerged as a pivotal factor in neurodegenerative pathologies, especially through its capacity to promote ferroptosis, a unique form of regulated cell death driven by iron-catalyzed lipid peroxidation. This review synthesizes current evidence on the molecular underpinnings of ferroptosis, focusing on how disruptions in iron homeostasis interact with key antioxidant defenses, such as the system Xc--glutathione-GPX4 axis, to tip neurons toward lethal oxidative damage. Building on these mechanistic foundations, we explore how ferroptosis intersects with hallmark pathologies in Alzheimer's disease (AD) and Parkinson's disease (PD) and examine how iron accumulation in vulnerable brain regions may fuel disease-specific protein aggregation and neurodegeneration. We further surveyed the distinct components of ferroptosis, highlighting the role of lipid peroxidation enzymes, mitochondrial dysfunction, and recently discovered parallel pathways that either exacerbate or mitigate neuronal death. Finally, we discuss how these insights open new avenues for neuroprotective strategies, including iron chelation and lipid peroxidation inhibitors. By highlighting open questions, this review seeks to clarify the current state of knowledge and proposes directions to harness ferroptosis modulation for disease intervention.

The transferrin receptor (TfR) is one of the key proteins involved in cellular iron uptake. TfR-mediated endocytosis of transferrin-bound iron is the major pathway for iron acquisition by most cells in the body. Over the past three decades, the studies on TfR have made significant progress, and also, our knowledge on cell iron uptake has greatly been improved. Here we focus on recent advances in the studies on TfR and a brief discussion of the structures and functions of four different types of TfR, namely TfR1 (transferrin receptor 1), TfR2 (transferrin receptor 2), TfR3 (glyceraldehyde-3-phosphate dehydrogenase) and TfR4 (cubilin). These proteins work in different cells or organs and at different times, ensuring that cells and tissues get the iron they need. Their normal expression and function are fundamental to the body's iron homeostasis.

Cardio-cerebrovascular diseases (CCVDs) are the leading cause of global mortality, yet effective treatment options remain limited. Ferroptosis, a novel form of regulated cell death, has emerged as a critical player in various CCVDs, including atherosclerosis, myocardial infarction, ischemia-reperfusion injury, cardiomyopathy, and ischemic/hemorrhagic strokes. This review highlights the core mechanisms of ferroptosis, its pathological implications in CCVDs, and the therapeutic potential of targeting this process. Additionally, it explores the role of Chinese herbal medicines (CHMs) in mitigating ferroptosis, offering novel therapeutic strategies for CCVDs management. Ferroptosis is regulated by several key pathways. The GPX4-GSH-System Xc- axis is central to ferroptosis execution, involving GPX4 using GSH to neutralize lipid peroxides, with system Xc- being crucial for GSH synthesis. The NAD(P)H/FSP1/CoQ10 axis involves FSP1 regenerating CoQ10 via NAD(P)H, inhibiting lipid peroxidation independently of GPX4. Lipid peroxidation, driven by PUFAs and enzymes like ACSL4 and LPCAT3, and iron metabolism, regulated by proteins like TfR1 and ferritin, are also crucial for ferroptosis. Inhibiting ferroptosis shows promise in managing CCVDs. In atherosclerosis, ferroptosis inhibitors reduce iron accumulation and lipid peroxidation. In myocardial infarction, inhibitors protect cardiomyocytes by preserving GPX4 and SLC7A11 levels. In ischemia-reperfusion injury, targeting ferroptosis reduces myocardial and cerebral damage. In diabetic cardiomyopathy, Nrf2 activators alleviate oxidative stress and iron metabolism irregularities. CHMs offer natural compounds that mitigate ferroptosis. They possess antioxidant properties, chelate iron, and modulate signaling pathways like Nrf2 and AMPK. For example, Salvia miltiorrhiza and Astragalus membranaceus reduce oxidative stress, while some CHMs chelate iron, reducing its availability for ferroptosis. In conclusion, ferroptosis plays a pivotal role in CCVDs, and targeting it offers novel therapeutic avenues. CHMs show promise in reducing ferroptosis and improving patient outcomes. Future research should explore combination therapies and further elucidate the molecular interactions in ferroptosis.

A local disruption of iron homeostasis leading to oxidative stress is considered one of the main mechanisms of asbestos-related genotoxicity. Another aspect contributing to the risk of developing pathological consequences upon asbestos exposure is individual genetic factors. In a previous study, we identified a coding SNP in the hephaestin gene (HEPH) that protects against developing asbestos-related thoracic cancer. Heph is a ferroxidase that promotes iron export in concert with the permease ferroportin (Fpn1). Here, we performed an in-depth functional characterization of the HephD568H variant to gain insights into the molecular basis of its protective activity. We showed that HephD568H forms a complex with Fpn1 and possesses full ferroxidase activity. Although HephD568H is more efficiently recruited to the plasma membrane, it is impaired in binding iron-deficient Tfn, whose interaction with wild-type (WT) ferroxidase emerged as a novel mechanism to perceive brain iron needs. Heph is expressed in the human lung by pericytes and fibroblasts, and lung pericytes were shown to respond to iron demand by upregulating the iron exporter pair. These results extend the paradigm of local iron regulation discovered at the blood-brain barrier to the pulmonary vasculature. Furthermore, they establish a mechanistic link between changes in iron sensing and the risk of developing asbestos-related malignancies.

Intestinal mucosal block is the transient reduction in iron absorption ability of intestinal epithelial cells (enterocytes) in response to previous iron exposures that occur at the cell scale. The block characteristics have been shown to depend both on iron exposure magnitude and temporality, and understanding block control will enable deeper understanding of how intestinal iron absorption contributes to pathological iron states. Three biochemical mechanisms implicated in driving the block behavior are divalent metal transporter 1 endocytosis, ferritin iron sequestration, and iron regulatory protein regulation of iron related protein expression. In this work, a model of enterocyte iron metabolism is built based on published experimental data that is capable of reproducing the mucosal block phenomena. The model is then used to estimate the quantitative contribution of each of the three mechanisms on the properties of the mucosal block. Analysis reveals that ferritin and iron regulatory proteins are the main intracellular mechanisms contributing to the mucosal block, findings congruent with experimental predictions. Lastly, DMT1 endocytosis is shown to play a role in limiting total iron uptake by enterocytes but does not contribute to the decrease in total iron transfer across their basal membrane seen in the mucosal block.

Transport of iron across the cell membrane is a tightly controlled process carried out by specific proteins in all living cells. In yeast and in mammals, a system formed by an enzyme with ferroxidase activity coupled to a membrane transporter supports iron uptake or iron efflux, respectively. Ferroxidase belongs to the family of blue multicopper oxidases, enzymes able to couple the one-electron oxidation of substrate(s) to full reduction of molecular oxygen to water. On the other hand, the permeases are widely different and are specific to Fe3+ and Fe2+ in yeast and multicellular organisms, respectively. This review will describe the yeast and human ferroxidase-permease systems, highlighting similarities and differences in structure, function and regulation of the respective protein components.

Iron plays a crucial role through various life stages of human. Iron homeostasis is primarily regulated by iron absorption which is mediated via divalent metal-ion transporter 1 (DMT1), and iron export protein ferroportin (FPN), as there is no active pathway for iron excretion from the body. Recent studies have shown that the magnitude of iron absorption changes through various life stages to meet changing iron requirements.

This review aims to provide an overview of recent researches on the regulation of iron absorption throughout mammalian life cycle, with the potential to reveal novel molecules and pathways at special stage of life. Such insights may pave the way for new treatments for disorders associated with aberrant iron homeostasis in the future.

This review first summarize the mechanism and regulation of iron absorption throughout various life stages, highlighting that regulatory mechanisms have developed to precisely align iron absorption to iron requirements. In adults, iron absorption is enhanced when body is deficient of iron, conversely, iron absorption is reduced when iron demand decreases via systemic regulator Hepcidin and cellular regulation. In the elderly, age-related inflammation, hormonal changes, and chronic diseases may affect the production of Hepcidin, affecting iron absorption. In infants, intestinal iron absorption and its regulatory mechanism are different from that in adults and there might be an alternative pathway independent of DMT1 and FPN due to high iron absorption. Unique to the fetus, iron is absorbed from maternal stores for its own use through the placenta and is regulated by maternal iron status. This review also proposes directions for further studies, offering promising avenues for developing new treatments for disorders associated with aberrant iron homeostasis.

A high-fat, iron (Fe)-deficient Western diet induces obesity and dysregulates Fe metabolism. We compared the influence of Lactiplantibacillus plantarum and Latilactobacillus curvatus with and without Fe supplementation on duodenal Fe uptake under high-fat diet conditions.

Rats were fed a high-fat diet (HF group) or high-fat, Fe-deficient diet (HFDEF group) or control diet (C group) for 8 wk. For the next 8 wk, the rats in the C and HF groups continued on the same diet, whereas the rats in the HFDEF group were divided into six groups and fed high-fat, Fe-deficient diet combinations with L. plantarum (Lp), L. curvatus (Lc), and Fe supplementation (HFDEF, HFDEFFe, HFDEFLp, HFDEFLc, HFDEFFeLp, HFDEFFeLc). Duodenum and serum samples were collected for analysis.

In the duodenum, the Fe content was higher in the HFDEFFeLp and HFDEFFeLc groups; the ferroportin level was higher in the HFDEFFeLp and HFDEFFeLc groups versus the HF group; the divalent metal transporter 1 level was higher in the HFDEFFeLc group versus the C and HF groups; and duodenal cytochrome B was higher in the HFDEFLc versus all the other groups. In addition, duodenal expression of the solute carrier family 11 member 2 gene was higher in the HFDEF group versus the C, HF, HFDEFFe, HFDEFFeLp, and HFDEFFeLc groups; that of the TFRC gene was higher in the HFDEFFeLc group versus the C, HF, HFDEF, and HFDEFFe groups; and that of the HJV gene was higher in the HFDEFFeLp group versus the C, HF, HFDEF, HFDEFFe, and HFDEFLc groups.

L. plantarum and L. curvatus supplementation shows some potential to enhance duodenal cellular Fe uptake in rats on a high-fat, Fe-deficient diet.

In the absence of physiological mechanisms to excrete excessive iron, the administration of iron chelation therapy is necessary. Age and hormones have an impact on the absorption, distribution, metabolism, and excretion of the medications used to treat iron excess, resulting in notable sex- and gender-related variances.

Here, we aimed to review the literature on sex and gender in iron overload assessment and treatment.

The development of iron chelators has shown to be a successful therapy for lowering the body's iron levels and averting the tissue damage and organ failure that follows. Numerous studies have described how individual factors can impact chelation treatment, potentially impact therapeutic response, and/or result in inadequate chelation or elevated toxicity; however, most of these data have not considered male and female patients as different groups, and particularly, the effect of hormonal variations in women have never been considered.

An effective iron chelation treatment should take into account sex and gender differences.

Osteoarthritis (OA) is a prevalent degenerative disease in elderly people that is characterized by cartilage loss and abrasion, leading to joint pain and dysfunction. The aetiology of OA is complicated and includes abnormal mechanical stress, a mild inflammatory environment, chondrocyte senescence and apoptosis, and changes in chondrocyte metabolism. Ferroptosis is a regulated cell death modality characterized by the excessive accumulation of lipid peroxidation and mitochondrial dysfunction. The role of ferroptosis in OA pathogenesis has aroused researchers' attention in the past two years, and there is mounting evidence indicating that ferroptosis is destructive. However, the impact of ferroptosis on OA and how the regulators of ferroptosis affect OA development are unclear. Here, we reviewed the current understanding of ferroptosis in OA pathogenesis and summarized several drugs and compounds targeting ferroptosis in OA treatment. The accumulation of intracellular iron, the trigger of Fenton reaction, the excessive production of ROS, the peroxidation of PUFA-PLs, and mitochondrial and membrane damage are involved in chondrocyte ferroptosis. System Xc - and GPX4 are the most important regulators that control ferroptosis. Several compounds, such as DFO and Fer-1, have been proven effective in preventing ferroptosis and slowing OA progression on animal models. Collectively, targeting ferroptosis shows great potential in treating OA.

Brain iron homeostasis plays a vital role in maintaining brain development and controlling neuronal function under physiological conditions. Many studies have shown that the imbalance of brain iron homeostasis is closely related to the pathogenesis of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD) and Parkinson's disease (PD). Recent advances have revealed the importance of iron transporters and regulatory molecules in the pathogenesis and treatment of NDs. This review summarizes the research progress on brain iron overload and the aberrant expression of several key iron transporters and regulators in AD and PD, emphasizes the pathological roles of these molecules in the pathogenesis of AD and PD, and highlights the therapeutic prospects of targeting these iron transporters and regulators to restore brain iron homeostasis in the treatment of AD and PD. A comprehensive understanding of the pathophysiological roles of iron, iron transporters and regulators, and their regulations in NDs may provide new therapeutic avenues for more targeted neurotherapeutic strategies for treating these diseases.

While the mechanisms by which tea consumption hinders iron absorption are well understood, tea-related anemia usually stems from prolonged and excessive intake, which obstructs iron absorption and depletes the body's iron reserves. Consequently, it is uncommon for hemoglobin levels to plummet by 6.9 g/dl solely due to moderate tea consumption over a span of three months. We present a case of severe iron-deficiency anemia in a woman following short-term, moderate green tea consumption. After modifying her tea intake regimen, there was no recurrence of anemia. Clinicians should be mindful that even moderate tea consumption can precipitate severe iron-deficiency anemia in individuals particularly vulnerable to its effects on iron absorption.

Neonatal iron deficiency anemia is prevalent among domestic pigs but does not occur in the offspring of wild boar. The main causes of this disorder in piglets of modern pig breeds are paucity of hepatic iron stores, high birth weight, and rapid growth. Replenishment of fetal iron stores is a direct result of iron transfer efficiency across the placenta. In this study, we attempted to investigate the molecular potential of iron transfer across the placenta as a possible cause of differences between wild boar and Polish Large White (PLW) offspring. Furthermore, by analyzing placentas from PLW gilts that had litters of different sizes, we aimed to elucidate the impact of the number of fetuses on placental ability to transport iron. Using RNA sequencing, we examined the expression of iron-related genes in the placentas from wild boar and PLW gilts. We did not reveal significant differences in the expression of major iron transporters among all analyzed placentas. However, in wild boar placentas, we found higher expression of copper-dependent ferroxidases such as ceruloplasmin, zyklopen, and hephaestin, which facilitate iron export to the fetal circulation. We also determined a close co-localization of ceruloplasmin and zyklopen with ferroportin, the only iron exporter.

Ferroptosis is a novel type of regulated cell death (RCD) involving iron accumulation and lipid peroxidation. Since its discovery in 2012, various studies have shown that ferroptosis is associated with the pathogenesis of various diseases. Ferroptotic cell death has also been linked to intestinal dysfunction but can act as either a positive or negative regulator of intestinal disease, depending on the cell type and disease context. The continued investigation of mechanisms underlying ferroptosis provides a wealth of potential for developing novel treatments. Considering the growing prevalence of intestinal diseases, particularly colorectal cancer (CRC) and inflammatory bowel disease (IBD), this review article focuses on potential therapeutics targeting the ferroptotic pathway in relation to CRC and IBD.

Cell death is one of the most important mechanisms of maintaining homeostasis in our body. Ferroptosis and pyroptosis are forms of necrosis-like cell death. These cell death modalities play key roles in the pathophysiology of cancer, cardiovascular, neurological diseases, and other pathologies. Transition metals are abundant group of elements in all living organisms. This paper presents a summary of ferroptosis and pyroptosis pathways and their connection to significant transition metals, namely zinc (Zn), copper (Cu), molybdenum (Mo), lead (Pb), cobalt (Co), iron (Fe), cadmium (Cd), nickel (Ni), mercury (Hg), uranium (U), platinum (Pt), and one crucial element, selenium (Se). Authors aim to summarize the up-to-date knowledge of this topic.In this review, there are categorized and highlighted the most common patterns in the alterations of ferroptosis and pyroptosis by transition metals. Special attention is given to zinc since collected data support its dual nature of action in both ferroptosis and pyroptosis. All findings are presented together with a brief description of major biochemical pathways involving mentioned metals and are visualized in attached comprehensive figures.This work concludes that the majority of disruptions in the studied metals' homeostasis impacts cell fate, influencing both death and survival of cells in the complex system of altered pathways. Therefore, this summary opens up the space for further research.

Kidney diseases pose a significant global health issue, frequently resulting in the gradual decline of renal function and eventually leading to end-stage renal failure. Abnormal iron metabolism and oxidative stress-mediated cellular dysfunction facilitates the advancement of kidney diseases. Iron homeostasis is strictly regulated in the body, and disturbance in this regulatory system results in abnormal iron accumulation or deficiency, both of which are associated with the pathogenesis of kidney diseases. Iron overload promotes the production of reactive oxygen species (ROS) through the Fenton reaction, resulting in oxidative damage to cellular molecules and impaired cellular function. Increased oxidative stress can also influence iron metabolism through upregulation of iron regulatory proteins and altering the expression and activity of key iron transport and storage proteins. This creates a harmful cycle in which abnormal iron metabolism and oxidative stress perpetuate each other, ultimately contributing to the advancement of kidney diseases. The crosstalk of iron metabolism and oxidative stress involves multiple signaling pathways, such as hypoxia-inducible factor (HIF) and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. This review delves into the functions and mechanisms of iron metabolism and oxidative stress, along with the intricate relationship between these two factors in the context of kidney diseases. Understanding the underlying mechanisms should help to identify potential therapeutic targets and develop novel and effective therapeutic strategies to combat the burden of kidney diseases.

The interaction of iron and intestinal flora, both of which play crucial roles in many physiologic processes, is involved in the development of Metabolic syndrome (MetS). MetS is a pathologic condition represented by insulin resistance, obesity, dyslipidemia, and hypertension. MetS-related comorbidities including type 2 diabetes mellitus (T2DM), obesity, metabolism-related fatty liver (MAFLD), hypertension polycystic ovary syndrome (PCOS), and so forth. In this review, we examine the interplay between intestinal flora and human iron metabolism and its underlying mechanism in the pathogenesis of MetS-related comorbidities. The composition and metabolites of intestinal flora regulate the level of human iron by modulating intestinal iron absorption, the factors associated with iron metabolism. On the other hand, the iron level also affects the abundance, composition, and metabolism of intestinal flora. The crosstalk between these factors is of significant importance in human metabolism and exerts varying degrees of influence on the manifestation and progression of MetS-related comorbidities. The findings derived from these studies can enhance our comprehension of the interplay between intestinal flora and iron metabolism, and open up novel potential therapeutic approaches toward MetS-related comorbidities.

Iron is an essential nutrient for growth among all branches of life, but while iron is among the most common elements, bioavailable iron is a relatively scarce nutrient. Since iron is fundamental for several biological processes, iron deficiency can be deleterious. On the other hand, excess iron may lead to cell and tissue damage. Consequently, iron balance is strictly regulated. As iron excretion is not physiologically controlled, systemic iron homeostasis is maintained at the level of absorption, which is mainly influenced by the amount of iron stores and the level of erythropoietic activity, the major iron consumer. Here, we outline recent advances that increased our understanding of the molecular aspects of iron absorption. Moreover, we examine the impact of these recent insights on dietary strategies for maintaining iron balance.

The redox reactivity of iron is a double-edged sword for cell functions, being either essential or harmful depending on metal concentration and location. Deregulation of iron homeostasis is associated with several clinical conditions, including viral infections. Clinical studies as well as in silico, in vitro and in vivo models show direct effects of several viruses on iron levels. There is support for the strategy of iron chelation as an alternative therapy to inhibit infection and/or viral replication, on the rationale that iron is required for the synthesis of some viral proteins and genes. In addition, abnormal iron levels can affect signaling immune response. However, other studies report different effects of viral infections on iron homeostasis, depending on the class and genotype of the virus, therefore making it difficult to predict whether iron chelation would have any benefit. This review brings general aspects of the relationship between iron homeostasis and the nonspecific immune response to viral infections, along with its relevance to the progress or inhibition of the inflammatory process, in order to elucidate situations in which the use of iron chelators could be efficient as antivirals.

Cells require micronutrients for numerous basic functions. Among these, iron, copper, and selenium are particularly critical for redox metabolism, and their importance is heightened during oncogene-driven perturbations in cancer. In this review, which particularly focuses on iron, we describe how these micronutrients are carefully chaperoned about the body and made available to tissues, a process that is designed to limit the toxicity of free iron and copper or by-products of selenium metabolism. We delineate perturbations in iron metabolism and iron-dependent proteins that are observed in cancer, and describe the current approaches being used to target iron metabolism and iron-dependent processes.

Chronic kidney disease (CKD) has become a global public health problem with high morbidity and mortality. Renal fibrosis can lead to end-stage renal disease (ESRD). However, there is still no effective treatment to prevent or delay the progression of CKD into ESRD. Therefore, exploring the pathogenesis of CKD is essential for preventing and treating CKD. There are a variety of trace elements in the human body that interact with each other within a complex regulatory network. Iron and copper are both vital trace elements in the body. They are critical for maintaining bodily functions, and the dysregulation of their metabolism can cause many diseases, including kidney disease. Ferroptosis is a new form of cell death characterized by iron accumulation and lipid peroxidation. Studies have shown that ferroptosis is closely related to kidney disease. However, the role of abnormal copper metabolism in kidney disease and its relationship with ferroptosis remains unclear. Here, our current knowledge regarding copper metabolism, its regulatory mechanism, and the role of abnormal copper metabolism in kidney diseases is summarized. In addition, we discuss the relationship between abnormal copper metabolism and ferroptosis to explore the possible pathogenesis and provide a potential therapeutic target for CKD.

The stimulation of host iron absorption is a promising antianemia strategy adjunctive/alternative to iron intervention. Here, gum arabic (GA) containing 3.14 ± 0.56% hydroxyproline-rich protein with repetitive X-(Pro/Hyp)n motifs was found to increase iron reduction, uptake, and transport to upregulate duodenal cytochrome b (Dcytb), divalent metal transporter 1 (DMT1), ferroportin, and hephaestin to inhibit hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) and to stabilize HIF2α in polarized Caco-2 cell monolayers in a dose-dependent manner, and this was dependent on its protein fraction, rather than the polysaccharide fraction. Three abundant GA-derived hydroxyproline-containing dipeptides of Hyp-Hyp, Pro-Hyp, and Ser-Hyp were detected by liquid chromatography-mass spectrometry in the lysates of polarized Caco-2 cell monolayers at the maximum levels of  0.167 ± 0.021, 0.134 ± 0.017, and 0.089 ± 0.015 μg/mg of protein, respectively, and showed desirable docking affinity energy values of -7.53, - 7.91, and -7.39 kcal/mol, respectively, against human PHD3. GA-derived peptides also acutely increased duodenal HIF2α stability and Dcytb, DMT1, ferroportin, and hephaestin transcription in rats (P < 0.05). Overall, GA-derived hydroxyproline-rich peptides stimulated intestinal iron absorption via PHD inhibition, HIF2α stabilization, and subsequent upregulation of iron transport proteins.

Iron physiology is regulated by a complex interplay of extracellular transport systems, coordinated transcriptional responses, and iron efflux mechanisms. Dysregulation of iron metabolism can result in defects in myelination, neurotransmitter synthesis, and neuronal maturation. In neonates, germinal matrix-intraventricular hemorrhage (GMH-IVH) causes iron overload as a result of blood breakdown in the ventricles and brain parenchyma which can lead to post-hemorrhagic hydrocephalus (PHH). However, the precise mechanisms by which GMH-IVH results in PHH remain elusive. Understanding the molecular determinants of iron homeostasis in the developing brain may lead to improved therapies. This manuscript reviews the various roles iron has in brain development, characterizes our understanding of iron transport in the developing brain, and describes potential mechanisms by which iron overload may cause PHH and brain injury. We also review novel preclinical treatments for IVH that specifically target iron. Understanding iron handling within the brain and central nervous system may provide a basis for preventative, targeted treatments for iron-mediated pathogenesis of GMH-IVH and PHH.

Cnidarians face significant threats from ocean acidification (OA) and anthropogenic pollutants such as oxybenzone (BP-3). The convergence of threats from multiple stressors is an important area to investigate because of potential significant synergistic or antagonistic interactions. Real-time quantitative PCR was performed to characterize the expression profiles of twenty-two genes of interest (GOI) in sea anemones (Exaiptasia diaphana) exposed to one of four treatments: 1) 96 h of OA conditions followed by a 4 h exposure to 20 ppb BP-3; 2) Exposure to 4 h 20 ppb BP-3 without 96 h of OA; 3) Exposure to 96 h of OA alone; or 4) laboratory conditions with no exposure to BP-3 and/or OA. These 22 GOIs represent cellular processes associated with proton-dependent transport, sodium-dependent transport, metal cation binding/transport, extracellular matrix, amino acid metabolism/transport, immunity, and/or steroidogenesis. These 22 GOIs provide new insight into vulnerable cellular processes in non-calcifying anthozoans exposed to OA and BP-3. Expression profiles were categorized as synergistic, antagonistic, or additive of BP-3 in the presence of OA. Two GOIs were synergistic. Fifteen GOIs were antagonistic and the remaining five GOIs were additive in response to BP-3 in acidified seawater. A subset of these GOIs appear to be candidate biomarkers for future in situ investigations. In human health, proton-dependent monocarboxylate transporters (MCTs) are promising pharmacological targets and recognized as potential biomarkers. By comparison, these same MCTs appear to be targets of xenobiotic chemical pollutants in cnidarian physiology. In the presence of BP-3, a network of collagen synthesis genes are upregulated and antagonistic in their expression profiles. Cytochrome b561 is a critical protein required for collagen synthesis and in silico modeling demonstrates BP-3 binds in the pocket of cytochrome b561. Understanding the underlying molecular mechanisms of "drug-like" compounds such as BP-3 may lead to a more comprehensive interpretation of transcriptional expression profiles. The collective antagonistic responses of GOIs associated with collagen synthesis strongly suggests these GOIs should be considered candidate biomarkers of effect. GOIs with synergistic and additive responses represent candidate biomarkers of exposure. Results show the effects of OA and BP-3 are interactive with respect to their impact on cnidarians. This investigation offers mechanistic data that supports the expression profiles and underpins higher order physiological responses.

Mammalian cells contain thousands of metalloproteins and evolved systems to correctly incorporate metal cofactors into their designated sites. Among the transient metals in living cells, iron is the most abundant element that present as an iron sulfur cluster, mono- and dinuclear iron centers or heme for catalytic reactions. Iron homeostasis is tightly regulated by intestinal iron absorption in mammals owing to the lack of an iron excretive transport system, apart from superficial epithelial cell detachment and urinary outflow reabsorptive impairment. In mammals, the central site for iron absorption is in the duodenum, where the divalent metal transporter 1 is essential for iron uptake. The most notable manifestation of mutated divalent metal transporter 1 presents as iron deficiency anemia in humans. In contrast, the mutation of ferroportin, which exports iron, causes iron overload by either gain or loss of function. Furthermore, hepcidin secretion from the liver suppresses iron efflux by internalizing and degrading ferroportin; thus, the hepcidin/ferroportin axis is extensively investigated for its potential as a therapeutic target to treat iron overload. This review focuses on the divalent metal transporter 1-mediated intestinal iron uptake and hepcidin/ferroportin axis that regulate systemic iron homeostasis.

Iron is a vital trace element for almost all organisms, and maintaining iron homeostasis is critical for human health. In mammals, the only known gatekeeper between intestinally absorbed iron and circulatory blood plasma is the membrane transporter ferroportin (Fpn). As such, dysfunction of Fpn or its regulation is a key driver of iron-related pathophysiology. This review focuses on discussing recent insights from high-resolution structural studies of the Fpn protein family. While these studies have unveiled crucial details of Fpn regulation and structural architecture, the associated functional studies have also at times provided conflicting data provoking more questions than answers. Here, we summarize key findings and illuminate important remaining questions and contradictions.

Iron is an essential metal element for organisms, whose metabolism is regulated by many genes and also dietary iron sources. However, the characterization, distribution and the responses of iron metabolism-related genes to different iron sources were not clear in fish.

The full-length cDNA sequences of fifteen iron metabolism-relevant genes (tf, tfr1, hp, fpn1, ho1, ho2, tfr2, hjv, hepcidin, fth, ftl, ftm, irp1, irp2 and hif2α.) were obtained via 3' and 5' RACE PCR from yellow catfish, a widely distributed freshwater teleost in China and other Asian countries. Their molecular characterizations were analyzed via the bioinformatic methods. Real-time quantitative PCR was used to explore their mRNA distribution in nine tissues. Their mRNA expression responses in four tissues (heart, brain, kidney and gill) were explored in yellow catfish fed diets with five iron sources, including ferrous sulfate (FeSO4), ferrous bisglycinate (Fe-Gly), ferrous chloride (FeCl2), ferric citrate (Fe-CA) and ferric oxide nanoparticles (Fe2O3NPs).

Compared with mammals and other teleost, these members shared similar domains. Their mRNAs were expressed in nine tested tissues, but mRNA levels varied. Yellow catfish fed the diets containing Fe-Gly and Fe2O3NPs had higher iron contents in heart, brain, kidney and gill. Meantime, different dietary iron sources addition affected their mRNA expression differentially in brain, heart, kidney and gill. It should be pointed out that only three biological replicate tanks were used in the present feeding treatment, and more biological replicate tanks (more than five) should be emphasized in further researches.

Taken together, our study identified fifteen iron metabolism-relevant genes, explored their mRNA expression in nine tissues, and their mRNA expression in the responses to different dietary iron sources in four tissues, indicating their important regulatory function in iron metabolism and homeostasis.

The presented review is an updating of Iron metabolism in context of normal physiology and pathological phases. Iron is one of the vital elements in humans and associated into proteins as a component of heme (e.g. hemoglobin, myoglobin, cytochromes proteins, myeloperoxidase, nitric oxide synthetases), iron sulfur clusters (e.g. respiratory complexes I-III, coenzyme Q10, mitochondrial aconitase, DNA primase), or other functional groups (e.g. hypoxia inducible factor prolyl hydroxylases). All these entire iron-containing proteins ar e needed for vital cellular and organismal functions together with oxygen transport, mitochondrial respiration, intermediary and xenobiotic metabolism, nucleic acid replication and repair, host defense, and cell signaling.

Cells have developed metabolic strategies to import and employ iron safely. Regulatory process of iron uptake, storage, intracellular trafficking and utilization is vital for the maintenance of cellular iron homeostasis. Cellular iron utilization and intracellular iron trafficking pathways are not well established and very little knowledge about this. The predominant organs, which are associated in the metabolism of iron, are intestine, liver, bone marrow and spleen. Iron is conserved, recycled and stored. The reduced bioavailability of iron in humans has developed extremely efficient mechanisms for iron conservation. Prominently, the losses of iron cannot considerably enhance through physiologic mechanisms, even if iron intake and stores become excessive. Loss of iron is balanced or maintained from dietary sources.

Numerous physiological abnormalities are associated with impaired iron metabolism. These abnormalities are appeared in the form of several diseases. There are duodenal ulcer, inflammatory bowel disease, sideroblastic anaemia, congenital dyserythropoietic anemias and low-grade myelodysplastic syndromes. Hereditary hemochromatosis and anaemia are two chronic diseases, which are responsible for disturbing the iron metabolism in various tissues, including the spleen and the intestine. Impairment in hepatic hepcidin synthesis is responsible for chronic liver disease, which is grounding from alcoholism or viral hepatitis. This condition directs to iron overload that can cause further hepatic damage. Iron has important role in several infectious diseases are tuberculosis, malaria trypanosomatid diseases and acquired immunodeficiency syndrome (AIDS). Iron is also associated with Systemic lupus erythematosus [SLE], cancer, Alzheimer's disease (AD) and post-traumatic epilepsy.

Recently, numerous research studies are gradually more dedicated in the field of iron metabolism, but a number of burning questions are still waiting for answer. Cellular iron utilization and intracellular iron trafficking pathways are not well established and very little knowledge about this. Increased information of the physiology of iron homeostasis will support considerate of the pathology of iron disorders and also make available the support to advance treatment.

Copper (Cu) is a trace element, essential for fish growth. In the current study, in addition to growth performance, we first explored the effects of Cu on collagen synthesis and myofiber growth and development in juvenile grass carp (Ctenopharyngodon idella). A total of 1080 fish (11.16 ± 0.01 g) were randomly divided into 6 treatments (3 replicates per treatment) to receive five doses of organic Cu, which were Cu citrate (CuCit) at 0.99 (basal diet), 2.19, 4.06, 6.15, and 8.07 mg/kg, and one dose of inorganic Cu (CuSO4·5H2O at 3.15 mg/kg), for 9 weeks. The results showed appropriate Cu level (4.06 mg/kg) enhanced growth performance, improved nutritional Cu status, and downregulated Cu-transporting ATPase 1 mRNA levels in the hepatopancreas, intestine, and muscle of juvenile grass carp. Meanwhile, collagen content in fish muscle was increased after Cu intake, which was probably due to the following pathways: (1) activating CTGF/TGF-β1/Smads signaling pathway to regulate collagen transcription; (2) upregulating of La ribonucleoprotein domain family 6 (LARP6) mRNA levels to regulate translation initiation; (3) increasing proline hydroxylase, lysine hydroxylase, and lysine oxidase activities to regulate posttranslational modifications. In addition, optimal Cu group increased myofiber diameters and the frequency of myofibers with diameter >50 μm, which might be associated with upregulation of cyclin B, cyclin D, cyclin E, proliferating cell nuclear antigen, myogenic determining factor (MyoD), myogenic factor 5, myogenin (MyoG), myogenic regulatory factor 4 and myosin heavy chain (MyHC) and downregulation of myostatin mRNA levels, increasing protein levels of MyoD, MyoG and MyHC in fish muscle. Finally, based on percentage weight gain (PWG), serum ceruloplasmin (Cp) activity and collagen content in fish muscle, Cu requirements were determined as 4.74, 4.37 and 4.62 mg/kg diet (CuCit as Cu source) of juvenile grass carp, respectively. Based on PWG and Cp activity, compared to CuSO4·5H2O, the efficacy of CuCit were 131.80% and 115.38%, respectively. Our findings provide new insights into Cu supplementation to promote muscle growth in fish, and help improve the overall productivity of aquaculture.

Iron accumulation in the CNS occurs in many neurological disorders. It can contribute to neuropathology as iron is a redox-active metal that can generate free radicals. The reasons for the iron buildup in these conditions are varied and depend on which aspects of iron influx, efflux, or sequestration that help maintain iron homeostasis are dysregulated. Iron was shown recently to induce cell death and damage via lipid peroxidation under conditions in which there is deficient glutathione-dependent antioxidant defense. This form of cell death is called ferroptosis. Iron chelation has had limited success in the treatment of neurological disease. There is therefore much interest in ferroptosis as it potentially offers new drugs that could be more effective in reducing iron-mediated lipid peroxidation within the lipid-rich environment of the CNS. In this review, we focus on the molecular mechanisms that induce ferroptosis. We also address how iron enters and leaves the CNS, as well as the evidence for ferroptosis in several neurological disorders. Finally, we highlight biomarkers of ferroptosis and potential therapeutic strategies.

In the last 15 years, among the many reasons given for the development of idiopathic forms of Parkinson's disease (PD), copper imbalance has been identified as a factor, and PD is often referred to as a copper-mediated disorder. More than 640 papers have been devoted to the relationship between PD and copper status in the blood, which include the following markers: total copper concentration, enzymatic ceruloplasmin (Cp) concentration, Cp protein level, and non-ceruloplasmin copper level. Most studies measure only one of these markers. Therefore, the existence of a correlation between copper status and the development of PD is still debated. Based on data from the published literature, meta-analysis, and our own research, it is clear that there is a connection between the development of PD symptoms and the number of copper atoms, which are weakly associated with the ceruloplasmin molecule. In this work, the link between the risk of developing PD and various inborn errors related to copper metabolism, leading to decreased levels of oxidase ceruloplasmin in the circulation and cerebrospinal fluid, is discussed.

Pregnancy entails a large negative balance of iron, an essential micronutrient. During pregnancy, iron requirements increase substantially to support both maternal red blood cell expansion and the development of the placenta and fetus. As insufficient iron has long been linked to adverse pregnancy outcomes, universal iron supplementation is common practice before and during pregnancy. However, in high-resource countries with iron fortification of staple foods and increased red meat consumption, the effects of too much iron supplementation during pregnancy have become a concern because iron excess has also been linked to adverse pregnancy outcomes. In this review, we address physiologic iron homeostasis of the mother, placenta, and fetus and discuss perturbations in iron homeostasis that result in pathological pregnancy. As many mechanistic regulatory systems have been deduced from animal models, we also discuss the principles learned from these models and how these may apply to human pregnancy.

Erythroblasts possess unique characteristics as they undergo differentiation from hematopoietic stem cells. During terminal erythropoiesis, these cells incorporate large amounts of iron in order to generate hemoglobin and ultimately undergo enucleation to become mature red blood cells, ultimately delivering oxygen in the circulation. Thus, erythropoiesis is a finely tuned, multifaceted process requiring numerous properly timed physiological events to maintain efficient production of 2 million red blood cells per second in steady state. Iron is required for normal functioning in all human cells, the erythropoietic compartment consuming the majority in light of the high iron requirements for hemoglobin synthesis. Recent evidence regarding the crosstalk between erythropoiesis and iron metabolism sheds light on the regulation of iron availability by erythroblasts and the consequences of insufficient as well as excess iron on erythroid lineage proliferation and differentiation. In addition, significant progress has been made in our understanding of dysregulated iron metabolism in various congenital and acquired malignant and non-malignant diseases. Finally, we report several actual as well as theoretical opportunities for translating the recently acquired robust mechanistic understanding of iron metabolism regulation to improve management of patients with disordered erythropoiesis, such as anemia of chronic inflammation, β-thalassemia, polycythemia vera, and myelodysplastic syndromes.

Cadmium (Cd) is an environmental pollutant that damages various tissues. Cd may cause a depletion of iron stores and subsequently an iron deficiency state in the liver. However, the molecular mechanism of decreased iron accumulation in the liver induced by long-term exposure to Cd is unknown. In this study, we investigated the hepatic accumulation of iron and the proximal duodenal expression of the genes involved in iron transport using mice chronically exposed to Cd. Five-week-old female C57BL/6J mice were fed a diet containing 300 ppm Cd for 12, 15, 19 and 21 months. The iron concentration in the liver was markedly decreased by Cd. Among iron-transport-related genes in the proximal duodenum, the gene expression of HCP1 and Cybrd1 was significantly decreased by Cd. HCP1 is an influx transporter of heme iron. Cybrd1 is a reductase that allows non-heme iron to enter cells. The expression of iron-transport-related genes on the duodenal basolateral membrane side was hardly altered by Cd. These results suggest that long-term exposure to Cd suppresses the expression of HCP1 and Cybrd1 in the proximal duodenum, resulting in reduced iron absorption and iron accumulation in the liver.

In a previous report, a 39-year-old patient with high serum iron levels from hereditary hemochromatosis (HH) was diagnosed with a form of retinal degeneration called bull's eye maculopathy. This is atypical for patients with HH, so it was theorized that the low serum levels of ferroxidase ceruloplasmin (CP) of this patient coupled with the high iron levels led to the retinal degeneration. CP, by oxidizing iron from its ferrous to ferric form, helps prevent the oxidative damage caused by ferrous iron. To test this, a hepcidin knockout (KO) mouse model of HH was combined with Cp KO to test whether the combination would lead to more severe retinal degeneration. Monthly in vivo retinal images were acquired and, after 11 months, mice were euthanized for further analyses. Both heterozygous and homozygous Cp KO increased the rate and severity of retinal degeneration. These results demonstrate the protective role of CP, which is most likely owing to its ferroxidase activity. The findings suggest that CP levels may influence the severity of retinal degeneration, especially in individuals with high serum iron.

Iron is by far the most widespread and essential transition metal, possessing crucial biological functions for living systems. Despite chemical advantages, iron biology has forced organisms to face with some issues: ferric iron insolubility and ferrous-driven formation of toxic radicals. For these reasons, acquisition and transport of iron constitutes a formidable challenge for cells and organisms, which need to maintain adequate iron concentrations within a narrow range, allowing biological processes without triggering toxic effects. Higher organisms have evolved extracellular carrier proteins to acquire, transport and manage iron. In recent years, a renewed interest in iron biology has highlighted the role of iron-proteins dysregulation in the onset and/or exacerbation of different pathological conditions. However, to date, no resolutive therapy for iron disorders has been found. In this review, we outline the efficacy of Lactoferrin, a member of the transferrin family mainly secreted by exocrine glands and neutrophils, as a new emerging orchestrator of iron metabolism and homeostasis, able to counteract iron disorders associated to different pathologies, including iron deficiency and anemia of inflammation in blood, Parkinson and Alzheimer diseases in the brain and cystic fibrosis in the lung.

The mammalian multicopper ferroxidases (MCFs) ceruloplasmin (CP), hephaestin (HEPH) and zyklopen (ZP) comprise a family of conserved enzymes that are essential for body iron homeostasis. Each of these enzymes contains six biosynthetically incorporated copper atoms which act as intermediate electron acceptors, and the oxidation of iron is associated with the four electron reduction of dioxygen to generate two water molecules. CP occurs in both a secreted and GPI-linked (membrane-bound) form, while HEPH and ZP each contain a single C-terminal transmembrane domain. These enzymes function to ensure the efficient oxidation of iron so that it can be effectively released from tissues via the iron export protein ferroportin and subsequently bound to the iron carrier protein transferrin in the blood. CP is particularly important in facilitating iron release from the liver and central nervous system, HEPH is the major MCF in the small intestine and is critical for dietary iron absorption, and ZP is important for normal hair development. CP and HEPH (and possibly ZP) function in multiple tissues. These proteins also play other (non-iron-related) physiological roles, but many of these are ill-defined. In addition to disrupting iron homeostasis, MCF dysfunction perturbs neurological and immune function, alters cancer susceptibility, and causes hair loss, but, despite their importance, how MCFs co-ordinately maintain body iron homeostasis and perform other functions remains incompletely understood.

The peptide hormone hepcidin is central to the regulation of iron metabolism, influencing the movement of iron into the circulation and determining total body iron stores. Its effect on a cellular level involves binding ferroportin, the main iron export protein, preventing iron egress and leading to iron sequestration within ferroportin-expressing cells. Hepcidin expression is enhanced by iron loading and inflammation and suppressed by erythropoietic stimulation. Aberrantly increased hepcidin leads to systemic iron deficiency and/or iron restricted erythropoiesis as occurs in anemia of chronic inflammation. Furthermore, insufficiently elevated hepcidin occurs in multiple diseases associated with iron overload such as hereditary hemochromatosis and iron loading anemias. Abnormal iron metabolism as a consequence of hepcidin dysregulation is an underlying factor resulting in pathophysiology of multiple diseases and several agents aimed at manipulating this pathway have been designed, with some already in clinical trials. In this chapter, we assess the complex regulation of hepcidin, delineate the many binding partners involved in its regulation, and present an update on the development of hepcidin agonists and antagonists in various clinical scenarios.

Ferroptosis is a type of regulated cell death characterized by intracellular accumulation of iron and reactive oxygen species, inhibition of system Xc-, glutathione depletion, nicotinamide adenine dinucleotide phosphate oxidation and lipid peroxidation. Since its discovery and characterization in 2012, many efforts have been made to reveal the underlying mechanisms, modulating compounds, and its involvement in disease pathways. Ferroptosis inducers include erastin, sorafenib, sulfasalazine and glutamate, which, by inhibiting system Xc-, prevent the import of cysteine into the cells. RSL3, statins, Ml162 and Ml210 induce ferroptosis by inhibiting glutathione peroxidase 4 (GPX4), which is responsible for preventing the formation of lipid peroxides, and FIN56 and withaferin trigger GPX4 degradation. On the other side, ferroptosis inhibitors include ferrostatin-1, liproxstatin-1, α-tocopherol, zileuton, FSP1, CoQ10 and BH4, which interrupt the lipid peroxidation cascade. Additionally, deferoxamine, deferiprone and N-acetylcysteine, by targeting other cellular pathways, have also been classified as ferroptosis inhibitors. Increased evidence has established the involvement of ferroptosis in distinct brain diseases, including Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis, multiple sclerosis, and Friedreich's ataxia. Thus, a deep understanding of how ferroptosis contributes to these diseases, and how it can be modulated, can open a new window of opportunities for novel therapeutic strategies and targets. Other studies have shown a sensitivity of cancer cells with mutated RAS to ferroptosis induction and that chemotherapeutic agents and ferroptosis inducers synergize in tumor treatment. Thus, it is tempting to consider that ferroptosis may arise as a target mechanistic pathway for the treatment of brain tumors. Therefore, this work provides an up-to-date review on the molecular and cellular mechanisms of ferroptosis and their involvement in brain diseases. In addition, information on the main ferroptosis inducers and inhibitors and their molecular targets is also provided.

Due to the growing evidence of the importance of iron status in immune responses, the biomarkers of iron metabolism are of interest in novel Coronavirus Disease 2019 (COVID-19). The present prospective study was carried out to compare iron status indicated by levels of ferritin with the levels of two novel biomarkers related to iron homeostasis, hephaestin and hypoxia-inducible factors-1 (HIF-1α) in the serum of patients with COVID-19 in comparison with a control group.

Blood samples from 34 COVID-19 patients and from 43 healthy volunteers were collected and the levels of HEPH and HIF-1α were measured by ELISA and compared with levels of serum ferritin. COVID-19 patients had higher serum levels of ferritin than those levels in control group (P < 0.0001). Conversely levels of HIF-1α and HEPH in the COVID-19 group were significantly lower than those of control group (P < 0.0001 for both). An inverse correlation between hephaestin and ferritin as well as between HIF-1α and ferritin was found among all subjects (P < 0.0001), and among COVID-19 patients, but not to statistical significance.

Levels of hephaestin and HIF-1α were found to be inversely related levels of ferritin across all participants in the study, and to our knowledge this is the first report of hephaestin and HIF-1α as potential markers of iron status. Further studies are needed to corroborate the findings, utilizing a broader range of markers to monitor inflammatory as well as iron status.

Epilepsy is a chronic neurological degenerative disease with a high incidence, affecting all age groups. Refractory Epilepsy (RE) occurs in approximately 30-40% of cases with a higher risk of sudden unexpected death in epilepsy (SUDEP). Recent studies have shown that spontaneous seizures developed in epilepsy can be related to an increase in oxidative stress and reactive oxygen derivatives (ROS) production. Increasing ROS concentration causes lipid peroxidation, protein oxidation, destruction of nuclear genetic material, enzyme inhibition, and cell death by a mechanism known as "ferroptosis" (Fts). Inactivation of glutathione peroxidase 4 (GPX4) induces Fts, while oxidative stress is linked with increased intracellular free iron (Fe+2) concentration. Fts is also a non-apoptotic programmed cell death mechanism, where a hypoxia-inducible factor 1 alpha (HIF-141) dependent hypoxic stress-like condition appears to occur with accumulation of iron and cytotoxic ROS in affected cells. Assuming convulsive crises as hypoxic stress, repetitive convulsive/hypoxic stress can be an effective inducer of the "epileptic heart" (EH), which is characterized by altered autonomic function and a high risk of malignant or fatal bradycardia. We previously reported that experimental recurrent seizures induce cardiomyocyte Fts associated with SUDEP. Furthermore, several genes related to Fts and hypoxia have recently been identified in acute myocardial infarction. An emerging theme from recent studies indicates that inhibition of GPX4 through modulating expression or activities of the xCT antiporter system (SLC7A11) governs cell sensitivity to oxidative stress from ferroptosis. Furthermore, during hypoxia, an increased expression of stress transcriptional factor ATF3 can promote Fts induced by erastin in a HIF-141-dependent manner. We propose that inhibition of Fts with ROS scavengers, iron chelators, antioxidants, and transaminase inhibitors could provide a therapeutic effect in epilepsy and improve the prognosis of SUDEP risk by protecting the heart from ferroptosis.

The production of erythropoietin (EPO), the main regulator of erythroid differentiation, is regulated by hypoxia-inducible factor (HIF). HIF2α seems to be the principal regulator of EPO transcription, but HIF1α and 3α also may have additional influences on erythroid maturation. HIF is also involved in the regulation of iron, an essential component in erythropoiesis. Iron is essential for the organism but is also highly toxic, so its absorption and retention are strictly controlled. HIF also induces the synthesis of proteins involved in iron regulation, thereby ensuring the availability of iron necessary for hematopoiesis. Iron is a major component of hemoglobin and is also involved in erythrocyte differentiation and proliferation and in the regulation of HIF. Renal anemia is a condition in which there is a lack of stimulation of EPO synthesis due to decreased HIF expression. HIF prolyl hydroxylase inhibitors (HIF-PHIs) stabilize HIF and thereby allow it to be potent under normoxic conditions. Therefore, unlike erythropoiesis-stimulating agents, HIF-PHI may enhance iron absorption from the intestinal tract and iron supply from reticuloendothelial macrophages and hepatocytes into the plasma, thus facilitating the availability of iron for hematopoiesis. The only HIF-PHI currently on the market worldwide is roxadustat, but in Japan, five products are available. Clinical studies to date in Japan have also shown that HIF-PHIs not only promote hematopoiesis, but also decrease hepcidin, the main regulator of iron metabolism, and increase the total iron-binding capacity (TIBC), which indicates the iron transport capacity. However, concerns about the systemic effects of HIF-PHIs have not been completely dispelled, warranting further careful monitoring.

Severe anaemia and invasive bacterial infections remain important causes of hospitalization and death among young African children. The emergence and spread of antimicrobial resistance demand better understanding of bacteraemia risk factors to inform prevention strategies. Epidemiological studies have reported an association between severe anaemia and bacteraemia. In this review, we explore evidence that severe anaemia is associated with increased risk of invasive bacterial infections in young children. We describe mechanisms of iron dysregulation in severe anaemia that might contribute to increased risk and pathogenesis of invasive bacteria, recent advances in knowledge of how iron deficiency and severe anaemia impair immune responses to bacterial infections and vaccines, and the gaps in our understanding of mechanisms underlying severe anaemia, iron deficiency, and the risk of invasive bacterial infections.