Iron is necessary for the production of hemoglobin, a protein in red blood cells that carries oxygen from the lungs to the body's tissues.

Iron plays a key role in energy metabolism and is essential for the synthesis of ATP, the body's primary source of cellular energy.

Iron is involved in the production of white blood cells and antibodies, which support the body's immune system.

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Ferroptosis is an iron-dependent cell death pathway and participates in various diseases. Current evidence suggests that ferroptosis can obviously affect the function of blood cells. This paper aims to elaborate the role of ferroptosis in blood cells and related diseases. First, abnormal ferroptosis damages the developing red blood cells by breaking systemic iron homeostasis, leading to erythropoiesis suppression and anaemia. Ferroptosis mediates neutrophils recruitment and neutrophil extracellular trap formation (NETosis). In T-cells, ferroptosis induces a novel point of synergy between immunotherapy and radiotherapy. Additionally, ferroptosis may mediate B cells differentiation, antibody responses and lymphoma. Nevertheless, increased ferroptosis can ameliorate acute myeloid leukaemia and T-cell leukaemia/lymphoma by inducing iron-dependent cancer cells death. Besides, ferroptosis activates platelets by increasing P-selectin, thus causing thromboembolism. Ferroptosis mediates virus infection and parasite infection by driving T-cell death and preventing T-cell immunity. Interestingly, ferroptosis is also considered as a critical player in COVID-19 infections, while targetting ferroptosis may also improve thromboembolism and prognosis in patients with COVID-19 infection. Overall, the crucial role of ferroptosis in blood cells will show a new therapeutic potential in blood cell-related diseases.HighlightsFerroptosis shows a new therapeutic potential for blood cell-related diseases.Ferroptosis damages erythropoiesis and thus induces anaemia.Ferroptosis induces platelet activation and leads to thromboembolism.Ferroptosis regulates T-cell and B-cell immunity, which participant in infectious diseases.Inversely, ferroptosis ameliorates acute myeloid leukaemia and T-cell leukaemia.

Targetting ferroptosis for blood cell-related diseases.

Iron is an essential micronutrient for virtually all living cells. In infectious diseases, both invading pathogens and mammalian cells including those of the immune system require iron to sustain their function, metabolism and proliferation. On the one hand, microbial iron uptake is linked to the virulence of most human pathogens. On the other hand, the sequestration of iron from bacteria and other microorganisms is an efficient strategy of host defense in line with the principles of 'nutritional immunity'. In an acute infection, host-driven iron withdrawal inhibits the growth of pathogens. Chronic immune activation due to persistent infection, autoimmune disease or malignancy however, sequesters iron not only from infectious agents, autoreactive lymphocytes and neoplastic cells but also from erythroid progenitors. This is one of the key mechanisms which collectively result in the anemia of chronic inflammation. In this review, we highlight the most important interconnections between iron metabolism and immunity, focusing on host defense against relevant infections and on the clinical consequences of anemia of inflammation.

Iron in infection and immunity.

Anemia is common in elective surgery and is an independent risk factor for morbidity and mortality. Historical management of anemia has focused on the use of allogeneic blood transfusion but this in itself is not without risk. It too has been independently associated with morbidity and mortality, let alone the costs and relative shortage of this resource. In recognition of this, patient blood management (PBM) shifts the focus from the product to the patient and views the patient's own blood as a resource that should be conserved and managed appropriately as a standard of care. It consists of 3 pillars: the optimization of red blood cell mass; reduction of blood loss and bleeding; and optimization of the patient's physiological tolerance toward anemia. Integration of these 3 pillars in the form of multimodal care bundles and strategies into perioperative pathways should improve care processes and patient outcome. Preoperative anemia is most commonly caused by functional iron deficiency and should be treated with oral iron, intravenous iron, and/or recombinant erythropoietin. An individualized assessment of the thrombotic risk of discontinuing anticoagulant and antiplatelet medication should be balanced against the risk of perioperative bleeding. Neuraxial anesthetic techniques should be considered and minimally invasive surgery undertaken where appropriate. Cell salvage should be used if significant blood loss is anticipated and pharmacological treatments such as tranexamic acid and fibrin sealants have been shown to reduce blood loss. Point of care tests can guide the perioperative management of dynamic coagulopathy. Blood testing sampling should be performed only when indicated and when taken, sample volume and waste should be minimized. Restrictive blood transfusion thresholds and reassessment after single unit transfusion should be incorporated into clinical practice where appropriate. For PBM to become standard practice in routine surgical care, national health care quality change initiatives must set the agenda for change but the patient-centered approach to PBM should be delivered in a way that is also hospital centered. Characterization of the current practice of PBM at each hospital is crucial to facilitate the benchmarking of performance. Barriers to effective implementation such as lack of knowledge should be identified and acted on. Continuous audit of practice with a focus on transfusion rates and patient outcomes can identify areas in need of improvement and provide iterative feedback to motivate and inspire the main stakeholders.

Perioperative Patient Blood Management to Improve Outcomes.

Metals are essential components in all forms of life required for the function of nearly half of all enzymes and are critically involved in virtually all fundamental biological processes. Especially, the transition metals iron (Fe), zinc (Zn), manganese (Mn), nickel (Ni), copper (Cu) and cobalt (Co) are crucial micronutrients known to play vital roles in metabolism as well due to their unique redox properties. Metals carry out three major functions within metalloproteins: to provide structural support, to serve as enzymatic cofactors, and to mediate electron transportation. Metal ions are also involved in the immune system from metal allergies to nutritional immunity. Within the past decade, much attention has been drawn to the roles of metal ions in the immune system, since increasing evidence has mounted to suggest that metals are critically implicated in regulating both the innate immune sensing of and the host defense against invading pathogens. The importance of ions in immunity is also evidenced by the identification of various immunodeficiencies in patients with mutations in ion channels and transporters. In addition, cancer immunotherapy has recently been conclusively demonstrated to be effective and important for future tumor treatment, although only a small percentage of cancer patients respond to immunotherapy because of inadequate immune activation. Importantly, metal ion-activated immunotherapy is becoming an effective and potential way in tumor therapy for better clinical application. Nevertheless, we are still in a primary stage of discovering the diverse immunological functions of ions and mechanistically understanding the roles of these ions in immune regulation. This review summarizes recent advances in the understanding of metal-controlled immunity. Particular emphasis is put on the mechanisms of innate immune stimulation and T cell activation by the essential metal ions like calcium (Ca2+), zinc (Zn2+), manganese (Mn2+), iron (Fe2+/Fe3+), and potassium (K+), followed by a few unessential metals, in order to draw a general diagram of metalloimmunology.

Metalloimmunology: The metal ion-controlled immunity.

Iron overload causes progressive organ damage and is associated with arthritis, liver damage, and heart failure. Elevated iron levels are present in 1%-5% of individuals; however, iron overload is undermonitored and underdiagnosed. Genetic factors affecting iron homeostasis are emerging. Individuals with hereditary xerocytosis, a rare disorder with gain-of-function (GOF) mutations in mechanosensitive PIEZO1 ion channel, develop age-onset iron overload. We show that constitutive or macrophage expression of a GOF Piezo1 allele in mice disrupts levels of the iron regulator hepcidin and causes iron overload. We further show that PIEZO1 is a key regulator of macrophage phagocytic activity and subsequent erythrocyte turnover. Strikingly, we find that E756del, a mild GOF PIEZO1 allele present in one-third of individuals of African descent, is strongly associated with increased plasma iron. Our study links macrophage mechanotransduction to iron metabolism and identifies a genetic risk factor for increased iron levels in African Americans.

A role of PIEZO1 in iron metabolism in mice and humans.

Ferroptosis, a type of cell death involving iron and lipid peroxidation, has been found to be closely associated with the development of many diseases. Mitochondria are vital components of eukaryotic cells, serving important functions in energy production, cellular metabolism, and apoptosis regulation. Presently, the precise relationship between mitochondria and ferroptosis remains unclear. In this study, we aim to systematically elucidate the mechanisms via which mitochondria regulate ferroptosis from multiple perspectives to provide novel insights into mitochondrial functions in ferroptosis. Additionally, we present a comprehensive overview of how mitochondria contribute to ferroptosis in different conditions, including cancer, cardiovascular disease, inflammatory disease, mitochondrial DNA depletion syndrome, and novel coronavirus pneumonia. Gaining a comprehensive understanding of the involvement of mitochondria in ferroptosis could lead to more effective approaches for both basic cell biology studies and medical treatments.

Mitochondria-mediated Ferroptosis in Diseases Therapy: From Molecular Mechanisms to Implications.

Complex I (NADH:ubiquinone oxidoreductase) is crucial for respiration in many aerobic organisms. In mitochondria, it oxidizes NADH from the tricarboxylic acid cycle and β-oxidation, reduces ubiquinone, and transports protons across the inner membrane, contributing to the proton-motive force. It is also a major contributor to cellular production of reactive oxygen species. The redox reaction of complex I is catalyzed in the hydrophilic domain; it comprises NADH oxidation by a flavin mononucleotide, intramolecular electron transfer along a chain of iron-sulfur clusters, and ubiquinone reduction. Redox-coupled proton translocation in the membrane domain requires long-range energy transfer through the protein complex, and the molecular mechanisms that couple the redox and proton-transfer half-reactions are currently unknown. This review evaluates extant data on the mechanisms of energy transduction and superoxide production by complex I, discusses contemporary mechanistic models, and explores how mechanistic studies may contribute to understanding the roles of complex I dysfunctions in human diseases.

Mitochondrial complex I.

Optimising nutrition intake is a key component for supporting athletic performance and supporting adaption to training. Athletes often use micronutrient supplements in order to correct vitamin and mineral deficiencies, improve immune function, enhance recovery and or to optimise their performance. The aim of this review was to investigate the recent literature regarding micronutrients (specifically iron, vitamin C, vitamin E, vitamin D, calcium) and their effects on physical performance. Over the past ten years, several studies have investigated the impacts of these micronutrients on aspects of athletic performance, and several reviews have aimed to provide an overview of current use and effectiveness. Currently the balance of the literature suggests that micronutrient supplementation in well-nourished athletes does not enhance physical performance. Excessive intake of dietary supplements may impair the body's physiological responses to exercise that supports adaptation to training stress. In some cases, micronutrient supplementation is warranted, for example, with a diagnosed deficiency, when energy intake is compromised, or when training and competing at altitude, however these micronutrients should be prescribed by a medical professional. Athletes are encouraged to obtain adequate micronutrients from a wellbalanced and varied dietary intake.

Micronutrients and athletic performance: A review.

Meat represents an important source of high-quality dietary protein for a large proportion of the global population. In addition, red meat, in particular, significantly contributes to the intake of a wide range of micronutrients, including iron, zinc, selenium, vitamin D and vitamin B12. While these nutrients can be supplied in sufficient amounts by consumption of a range of fruit and vegetables, in many developing countries, where the availability of such foods may be limited, access to meat often protects against malnutrition and improves child cognitive development. Excessive consumption of meat and meat products is often associated with overconsumption of energy and fat, resulting in excess weight, obesity and an increased risk of chronic diseases, such as cardiovascular disease and type 2 diabetes. In addition, certain components of fresh and processed red meat may further increase the risk of these diseases and predispose the consumer to cancer, particularly colorectal cancer. In the face of population growth and global warming, there is increasing concern about the sustainability of farm animal production. Thus, while a modest intake of meat represents an important strategy to avoid essential nutrient deficiencies, limiting its intake can reduce the development of a range of chronic diseases and could have significant beneficial effects on global food security.

The effects of meat consumption on global health.

Iron plays a crucial role in the biochemistry and development of nearly all living organisms. Iron starvation of pathogens during infection is a striking feature utilized by a host to quell infection. In mammals and some other animals, iron is essentially obtained from diet and recycled from erythrocytes. Free iron is cytotoxic and is readily available to invading pathogens. During infection, most pathogens utilize host iron for their survival. Therefore, to ensure limited free iron, the host's natural system denies this metal in a process termed nutritional immunity. In this fierce battle for iron, hosts win over some pathogens, but others have evolved mechanisms to overdrive the host barriers. Production of siderophores, heme iron thievery, and direct binding of transferrin and lactoferrin to bacterial receptors are some of the pathogens' successful strategies which are highlighted in this review. The intricate interplay between hosts and pathogens in iron alteration systems is crucial for understanding host defense mechanisms and pathogen virulence. This review aims to elucidate the current understanding of host and pathogen iron alteration systems and propose future research directions to enhance our knowledge in this field.

Key players in the regulation of iron homeostasis at the host-pathogen interface.

Understanding of ferritin biology has traditionally centered on its role in iron storage and homeostasis, with low ferritin levels indicative of deficiency and high levels indicative of primary or secondary hemochromatosis. However, further work has shown that iron, redox biology and inflammation are inexorably linked. During infection, increased ferritin levels represent an important host defense mechanism that deprives bacterial growth of iron and protects immune cell function. It may also be protective, limiting the production of free radicals and mediating immunomodulation. Additionally, hyperferritinemia is a key acute-phase reactants, used by clinicians as an indication for therapeutic intervention, aimed at controlling inflammation in high-risk patients. One school of thought maintains that hyperferritinemia is an 'innocent bystander' biomarker of uncontrolled inflammation that can be used to gauge effectiveness of intervention. Other schools of thought maintain that ferritin induction could be a protective negative regulatory loop. Others maintain that ferritin is a key mediator of immune dysregulation, especially in extreme hyperferritinemia, via direct immune-suppressive and pro-inflammatory effects. There is a clear need for further investigation of the role of ferritin in uncontrolled inflammatory conditions both as a biomarker and mediator of disease because its occurrence identifies patients with high mortality risk and its resolution predicts their improved survival.

Hyperferritinemia and inflammation.

Iron is vital for many physiological functions, including energy production, and dysregulated iron homeostasis underlies a number of pathologies. Ferroptosis is a recently recognized form of regulated cell death that is characterized by iron dependency and lipid peroxidation, and this process has been reported to be involved in multiple diseases. The mechanisms underlying ferroptosis are complex, and involve both well-described pathways (including the iron-induced Fenton reaction, impaired antioxidant capacity, and mitochondrial dysfunction) and novel interactions linked to cellular energy production. In this review, we examine the contribution of iron to diverse metabolic activities and their relationship to ferroptosis. There is an emphasis on the role of iron in driving energy production and its link to ferroptosis under both physiological and pathological conditions. In conclusion, excess reactive oxygen species production driven by disordered iron metabolism, which induces Fenton reaction and/or impairs mitochondrial function and energy metabolism, is a key inducer of ferroptosis.

Double-edge sword roles of iron in driving energy production versus instigating ferroptosis.

The role of iron in the formation and functioning of erythrocytes, and to a lesser degree of white blood cells, is well established, but the relationship between iron and platelets is less documented. Physiologically, iron plays an important role in hematopoiesis, including thrombopoiesis; iron levels direct, together with genetic factors, the lineage commitment of megakaryocytic/erythroid progenitors toward either megakaryocyte or erythroid progenitors. Megakaryocytic iron contributes to cellular machinery, especially energy production in platelet mitochondria. Thrombocytosis, possibly favoring vascular thrombosis, is a classical feature observed with abnormally low total body iron stores (mainly due to blood losses or decreased duodenal iron intake), but thrombocytopenia can also occur in severe iron deficiency anemia. Iron sequestration, as seen in inflammatory conditions, can be associated with early thrombocytopenia due to platelet consumption and followed by reactive replenishment of the platelet pool with possibility of thrombocytosis. Iron overload of genetic origin (hemochromatosis), despite expected mitochondrial damage related to ferroptosis, has not been reported to cause thrombocytopenia (except in case of high degree of hepatic fibrosis), and iron-related alteration of platelet function is still a matter of debate. In acquired iron overload (of transfusional and/or dyserythropoiesis origin), quantitative or qualitative platelet changes are difficult to attribute to iron alone due to the interference of the underlying hematological conditions; likewise, hematological improvement, including increased blood platelet counts, observed under iron oral chelation is likely to reflect mechanisms other than the sole beneficial impact of iron depletion.

Iron and platelets: A subtle, under-recognized relationship.

In patients with chronic kidney disease, vitamin D insufficiency is highly prevalent. It can be corrected by supplementation with either vitamin D(2) or vitamin D3. Recent studies in patients without impaired kidney function suggest that vitamin D(3) is more efficient than vitamin D(2) in correcting vitamin D insufficiency. However, no direct comparison has been made in hemodialysis (HD) patients.

Vitamin D2 versus vitamin D3 supplementation in hemodialysis patients: a comparative pilot study.

Daily vitamin D supplementation is often inadequate in treating vitamin D deficiency due to poor compliance. A single, large dose of vitamin D given at timed intervals may be an alternative strategy.

Large, single-dose, oral vitamin D supplementation in adult populations: a systematic review.

Vitamin D, sunshine and UVB phototherapy were first reported in the early 1900s to control psoriasis, cure rickets and cure tuberculosis (TB). Vitamin D also controlled asthma and rheumatoid arthritis with intakes ranging from 60,000 to 600,000 International Units (IU)/day. In the 1980s, interest in treating psoriasis with vitamin D rekindled. Since 1985 four different oral forms of vitamin D (D2, D3, 1-hydroxyvitaminD3 (1(OH)D3) and 1,25-dihydroxyvitaminD3 (calcitriol)) and several topical formulations have been reported safe and effective treatments for psoriasis-as has UVB phototherapy and sunshine. In this review we show that many pre-treatment serum 25(OH)D concentrations fall within the current range of normal, while many post-treatment concentrations fall outside the upper limit of this normal (100 ng/mL). Yet, psoriasis patients showed significant clinical improvement without complications using these treatments. Current estimates of vitamin D sufficiency appear to underestimate serum 25(OH)D concentrations required for optimal health in psoriasis patients, while concentrations associated with adverse events appear to be much higher than current estimates of safe serum 25(OH)D concentrations. Based on these observations, the therapeutic index for vitamin D needs to be reexamined in the treatment of psoriasis and other diseases strongly linked to vitamin D deficiency, including COVID-19 infections, which may also improve safely with sufficient vitamin D intake or UVB exposure.

Oral and Topical Vitamin D, Sunshine, and UVB Phototherapy Safely Control Psoriasis in Patients with Normal Pretreatment Serum 25-Hydroxyvitamin D Concentrations: A Literature Review and Discussion of Health Implications.

Chiang, C-m, Ismaeel, A, Griffis, RB, and Weems, S. Effects of vitamin D supplementation on muscle strength in athletes: A systematic review. J Strength Cond Res 31(2): 566-574, 2017-The purpose of this systematic review of the literature was to investigate the effects of vitamin D supplementation on muscle strength in athletes. A computerized literature search of 3 databases (PubMed, MEDLINE, and Scopus) was performed. Included in the review were randomized controlled trials (RCTs), published in English, which measured serum vitamin D concentrations and muscle strength in healthy, athletic participants aged 18-45 years. Quality was assessed using the PEDro scale. Five RCTs and 1 controlled trial were identified, and quality assessment showed 5 trials were of "excellent quality" and 1 was of "good quality." Trials lasted from 4 weeks to 6 months and dosages ranged from 600 to 5,000 International Units (IU) per day. Vitamin D2 was found to be ineffective at impacting muscle strength in both studies wherein it was administered. In contrast, vitamin D3 was shown to have a positive impact on muscle strength. In 2 studies, strength outcome measures were significantly improved after supplementation (p ≤ 0.05). In the other 2 studies administering vitamin D3, there were trends for improved muscle strength. Specifically, improvements in strength ranged from 1.37 to 18.75%. Additional studies are needed to confirm these associations.

Effects of Vitamin D Supplementation on Muscle Strength in Athletes: A Systematic Review.

A 2017 meta-analysis of data from 25 randomised controlled trials (RCTs) of vitamin D supplementation for the prevention of acute respiratory infections (ARIs) revealed a protective effect of this intervention. We aimed to examine the link between vitamin D supplementation and prevention of ARIs in an updated meta-analysis.

Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials.

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