Iron — is too much more harmful than too little?

Aim of the study: Iron is an essential trace metal for nearly all infectious microorganisms, and host defense mechanisms target this dependence to deprive microbes of iron. This review highlights mechanisms that are activated during infections to restrict iron on mucosal surfaces, in plasma and extracellular fluid, and within macrophages.

Results: Iron is an essential trace metal for nearly all infectious microorganisms, and host defense mechanisms target this dependence to deprive microbes of iron. This review highlights mechanisms that are activated during infections to restrict iron on mucosal surfaces, in plasma and extracellular fluid, and within macrophages. Iron overload disorders, such as hereditary hemochromatosis or β-thalassemia, interfere with iron-restrictive host responses, and thereby cause increased susceptibility to infections with microbes that can exploit this vulnerability. Anemia of inflammation (formerly known as anemia of chronic diseases) is an "off-target" effect of host defense wherein inflammatory cytokines shorten erythrocyte lifespan by activating macrophages, prioritize leukocyte production in the marrow, and induce hepcidin to increase plasma transferrin saturation and the concentration of non-transferrin-bound iron.

Aim of the study: To characterize the functional role of Fth (ferritin H) in mediating cardiac iron homeostasis and heart disease.

Results: Mice expressing a conditional Fth knockout allele were crossed with 2 distinct Cre recombinase-expressing mouse lines, resulting in offspring that lack Fth expression specifically in myocytes (MCK-Cre) or cardiomyocytes (Myh6-Cre). Mice lacking Fth in cardiomyocytes had decreased cardiac iron levels and increased oxidative stress, resulting in mild cardiac injury upon aging. However, feeding these mice a high-iron diet caused severe cardiac injury and hypertrophic cardiomyopathy, with molecular features typical of ferroptosis, including reduced glutathione (GSH) levels and increased lipid peroxidation. Ferrostatin-1, a specific inhibitor of ferroptosis, rescued this phenotype, supporting the notion that ferroptosis plays a pathophysiological role in the heart. Finally, we found that Fth-deficient cardiomyocytes have reduced expression of the ferroptosis regulator Slc7a11, and overexpressing Slc7a11 selectively in cardiomyocytes increased GSH levels and prevented cardiac ferroptosis.

Aim of the study: Iron deficiency is the most common nutrient deficiency in the world, affecting over 20% of premenopausal women worldwide. Oral iron supplementation is often the first-line treatment for the acute and chronic management of iron deficiency due to its ease and accessibility.

Results: Unabsorbed iron propagates many of the side effects that complicate oral iron use including dyspepsia and constipation, all of which can thus be exacerbated by excessive oral iron doses. Daily low dose and every other day dosing protocols have attempted to bypass this physiologic bottleneck to allow for effective absorption and limit side effects; however, this approach has still resulted in low fractional iron absorption. In the following manuscript, we review the pathophysiology of iron absorption and current evidence for various preparations of oral iron. Lastly, we highlight opportunities for further study to advance the care of individuals affected by iron deficiency.

Aim of the study: Iron deficiency (ID) and iron-deficiency anaemia (IDA) are global public health concerns, most commonly afflicting children, pregnant women and women of childbearing age. Pathological outcomes of ID include delayed cognitive development in children, adverse pregnancy outcomes and decreased work capacity in adults.

Results: FeSO4 ); however, dosing at several-fold above the RDA may be required due to less efficient absorption. Excess enteral iron causes adverse gastrointestinal side effects, thus reducing compliance, and negatively impacts the gut microbiome. Recent research has sought to identify new iron formulations with better absorption so that lower effective dosing can be utilized. This article outlines emerging research on oral iron supplementation and focuses on molecular mechanisms by which different supplemental forms of iron are transported across the intestinal epithelium and whether these transport pathways are subject to regulation by the iron-regulatory hormone hepcidin.

Aim of the study: Iron is a necessary element for life; however, excess iron leads to oxidative stress by the Fenton reaction. Iron deficiency is prevalent in patients with heart failure, while iron overload is associated in the pathogenesis of atherosclerosis.

Results: Iron deficiency is prevalent in patients with heart failure, while iron overload is associated in the pathogenesis of atherosclerosis. These findings suggest the "iron paradox" in cardiovascular diseases. Iron metabolism in cardiovascular diseases is complex, and the mechanisms regulating systemic and cellular iron metabolism in cardiovascular diseases remain completely unknown. In this review, we focus on the role of iron in cardiovascular diseases.

Aim of the study: Iron, an essential trace element, plays a complex role in tumour biology. While iron causes cancer clearance through toxic free radical generation, iron-induced free radical flux also acts as a cancer promoter.

Results: The co-play of iron deficiency and overload along with iron's pro-tumour and antitumour roles with intersecting mechanisms, thus presents an unpredictable regulatory response loop in a state of malignancy. The relevance of iron's thresholds beyond which it proves to be beneficial against tumorigenesis hence becomes questionable. These factors pose a challenge, over establishing if iron chelation or iron flooding acts as a better approach towards antitumour therapies. This review presents a critical picture of multiple contrasting features of iron's behaviour in cancer, leading towards two conditions lying at opposite ends of a spectrum: iron deficiency and overload in chronic disease conditions including cancer, hence, validating the critical significance of diagnosis of patients' iron status prior to opting for subsequent therapies.

Aim of the study: Iron is essential for a healthy pregnancy, and multiple iron-regulatory mechanisms-maternal, placental and fetal-are involved in maintaining iron homeostasis during pregnancy. Iron disorders, particularly iron deficiency anaemia, are prevalent in women of reproductive age and represent the leading cause of years lived with disability in women worldwide.

Results: Despite this burden, routine screening for iron deficiency is uncommon, and early treatment prior to the development of anaemia is lacking. Although far less prevalent, iron overload is also associated with adverse outcomes. Further studies are needed to elucidate the effects of maternal iron overload on the placenta and fetus, its consequences for child development, and to inform improved management strategies for this underrecognized condition. The goal of this review is to summarize physiological iron requirements and regulatory mechanisms during pregnancy, evaluate the benefits and limitations of available biomarkers and therapies, and underscore the importance of early and repeated screening for iron deficiency throughout gestation.

Aim of the study: Congenital dyserythropoietic anemia (CDA) is a rare hereditary disorder marked by ineffective erythropoiesis and iron overload. Data on endocrine involvement in CDA remain limited.

Results: After excluding vitamin D deficiency, ferritin levels showed a significant positive correlation with the number of endocrine abnormalities (p = 0.015). No significant associations were observed between endocrine abnormalities and age, sex, or hemoglobin levels. Endocrine complications are common in CDA and are associated with iron overload, even in non-transfusion-dependent patients. Regular endocrine evaluation and careful monitoring of iron burden are essential for all patients with CDA.

Aim of the study: Acetaminophen (APAP) overdose is a leading cause of liver failure in Western countries and a major clinical challenge because effective treatment options remain limited for patients who present after the optimal early therapeutic window. Iron is distributed among several subcellular compartments, such as cytosol, mitochondria, ferritin, and endosomes/lysosomes.

Results: Emerging evidence indicates that intracellular iron homeostasis and organelle function may be critical during the regeneration phase for repairing liver damage. Our recent work identified the metalloreductase six-transmembrane epithelial antigen of the prostate 4 (STEAP4) as a critical regulator of lysosomal iron homeostasis and membrane integrity during the regeneration phase following APAP overdose. Hepatic STEAP4 deficiency promoted lysosomal iron accumulation and impaired hepatocyte proliferation, whereas deferiprone-mediated iron chelation restored lysosomal function and promoted liver regeneration. In this perspective, we discuss the potential of targeting lysosomal iron to promote liver repair after APAP overdose-induced liver injury, as well as the limitations and challenges.