Observational studies have shown a potential link between immune factors and the risk of iron deficiency anemia (IDA), yet the causal relationship between immune cells and IDA remains enigmatic. Herein, we used Mendelian randomization (MR) to assess whether this association is causal.

We selected IDA genetic variants, including 8376 samples and 9810691 single nucleotide polymorphisms, and immune cells from a large open genome-wide association study (GWAS) for a bidirectional MR study. The primary method was inverse variance weighting (IVW), and auxiliary analyses were MR-Egger, weighted median, simple mode and weighted mode. The reliability of the results was subsequently verified by heterogeneity and sensitivity analysis.

IVW method showed that 19 types of immune cells may be the risk factors of IDA, whereas 15 types of immune cells are the protective factors of IDA. Reverse MR analysis suggested that immune cells from upstream etiology of IDA are not involved in follow-up immune activities. Next, we selected 731 immune cell types as the results. The research revealed that IDA may result in a rise in 23 kinds of immune cells and a reduction in 12 kinds of immune cells. In addition, sensitivity analysis demonstrated no evidence of heterogeneity or horizontal pleiotropy.

From a genetic standpoint, our study suggests that specific immune cells may be involved in the occurrence of IDA. Inversely, IDA may also contribute to immune dysfunction, thus guiding future clinical investigations.

Increased levels of intratumoral free iron drive more aggressive behavior with the development of treatment resistance and spread in a range of cancers including prostate cancer (PCa). This phenotype is associated with an increase in TFRC expression and a decrease in FTH1, a profile supporting increased iron acquisition. In this study we investigated the anti-oncogenic effects of two small peptides (FT-002 and FT-005) that upregulate FTH1 expression and downregulate TFRC expression when combined with standard androgen receptor pathway inhibitors (ARPIs) in xenograft models of PCa in male athymic nude mice. The PC3 cell line was used to establish xenografts representing highly aggressive, androgen-resistant PCa and the LNCaP cell line as a model of androgen-sensitive PCa. Both peptides enhanced the anti-tumor efficacy of ARPI therapy. Efficacy was more marked with the combination of the second-generation APRI enzalutamide than the first-generation agent bicalutamide, a result consistent with known resistance mechanisms to different ARPI therapy. Further, the FT-peptide/enzalutamide combination drove tumor regression whereas enzalutamide monotherapy only slowed growth, even in the hormone-sensitive xenograft. The FT-002a-enzalutamide combination was more effective than FT-005 in reducing tumor mass and volume and modulating FTH1 and TFRC expression. The reversal by the peptides of this oncogenic expression pattern points to a reduction in the tumor free iron via increased iron storage in ferritin and a reduction in iron influx via the transferrin receptor. Peptide-mediated modulation of tumor iron metabolism may therefore offer a novel means to enhance ARPI efficacy and delay resistance in advanced prostate cancer.

It is now understood that iron crosses the blood-brain barrier via a complex metabolic regulatory network and participates in diverse critical biological processes within the central nervous system, including oxygen transport, energy metabolism, and the synthesis and catabolism of myelin and neurotransmitters. During brain development, iron is distributed throughout the brain, playing a pivotal role in key processes such as neuronal development, myelination, and neurotransmitter synthesis. In physiological aging, iron can selectively accumulate in specific brain regions, impacting cognitive function and leading to intracellular redox imbalance, mitochondrial dysfunction, and lipid peroxidation, thereby accelerating aging and associated pathologies. Furthermore, brain iron accumulation may be a primary contributor to neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Comprehending the role of iron in brain development, aging, and neurodegenerative diseases, utilizing iron-sensitive Magnetic Resonance Imaging (MRI) technology for timely detection or prediction of abnormal neurological states, and implementing appropriate interventions may be instrumental in preserving normal central nervous system function.

Cancer remains the second leading cause of death worldwide, emphasizing the critical need for effective treatment and control strategies. Essential minerals such as copper, iron, zinc, selenium, phosphorous, calcium, and magnesium are integral to various biological processes and significantly influence cancer progression through altered metabolic pathways. For example, dysregulated copper levels promote tumor growth, while cancer cells exhibit an increased dependency on iron for signaling and redox reactions. Zinc influences tumor development through pathways such as Akt-p21. Selenium, primarily through its role in selenoproteins, exhibits anticancer potential but may also contribute to tumor progression. Similarly, dietary phosphate exacerbates tumorigenesis, metastasis, and angiogenesis through signaling pathway activation. Calcium, the most abundant mineral in the body, is tightly regulated within cells, and its dysregulation is a hallmark of various cancers. Magnesium deficiency, on the other hand, promotes cancer progression by fostering inflammation and free radical-induced DNA mutations. Interestingly, magnesium also plays a dual role, with low levels enhancing epithelial-mesenchymal transition (EMT), a critical process in cancer metastasis. This complex interplay of essential minerals underscores their potential as therapeutic targets. Dysregulation of these minerals and their pathways could be exploited to selectively target cancer cells, offering novel therapeutic strategies. This review summarizes current research on the abnormal accumulation or depletion of these microelements in tumor biology, drawing evidence from animal models, cell lines, and clinical samples. We also highlight the potential of these minerals as biomarkers for cancer diagnosis and prognosis, as well as therapeutic approaches involving metal chelators, pharmacological agents, and nanotechnology. By highlighting the intricate roles of these minerals in cancer biology, we aim to inspire further research in this critical yet underexplored area of oncology.

COASY protein-associated neurodegeneration (CoPAN) is a rare autosomal recessive disorder within the Neurodegeneration with Brain Iron Accumulation spectrum, resulting from mutations in COASY. This gene encodes the bifunctional enzyme essential for the final steps of coenzyme A biosynthesis. To elucidate the pathophysiology and iron dyshomeostasis underlying CoPAN, we analyzed fibroblasts and human induced pluripotent stem (hiPS)-derived astrocytes from two patients carrying distinct COASY mutations. Our findings reveal that CoPAN fibroblasts display altered iron homeostasis, characterized by iron aggregates, elevated cytosolic labile iron pool, and impaired tubulin acetylation. Patients hiPS-derived astrocytes showed mitochondrial morphological abnormalities and compromised vesicular trafficking. Notably, both cell types demonstrated evidence of ferroptosis, but the astrocytes exhibited more pronounced iron accumulation and lipid peroxidation. These results demonstrate that astrocytes may more accurately recapitulate the pathological phenotype of CoPAN compared to fibroblasts. Interestingly, astrocytes exhibited different levels of iron accumulation concomitant with cellular senescence, indicating a possible role of iron-induced cellular senescence. This finding suggests that the accumulation of cytosolic iron, possibly caused by mitochondrial dysfunction, actively promotes senescence. Our data emphasize the potential therapeutic efficacy of drugs that enhance mitochondrial functionality to attenuate the effects of CoPAN.

Altitude training is a method among endurance athletes to enhance performance via hypoxia-induced adaptations. However, individual responses vary significantly, with some athletes even showing performance decrements. Iron metabolism and immune function may influence these adaptations, as hypoxia-induced erythropoiesis increases systemic iron demand, potentially affecting immune cells reliant on iron. This study investigated the interplay between hematological, iron, and immunological variables under controlled normobaric hypoxia. 15 highly trained athletes participated in a 21-day live-high-train-low training camp in a normobaric altitude house. Blood samples were collected pre- and post-camp and at four intermediate time points to measure hematological variables, iron metabolism variables, and immunological variables. Pre- and post-performance was assessed via VO2max tests. Statistical analyses included paired t-tests, Wilcoxon rank-sum test, Spearman correlations, and Granger causality analysis to explore systemic temporal interactions. VO2max increased significantly (p < 0.05) with large interindividual variability (2.4 ± 3.5 ml/min/kg). Hemoglobin concentration, erythrocytes, and the soluble transferrin receptor (sTfR) showed significant increases over time (p < 0.05), while ferritin peaked early and declined post-camp. Myeloperoxidase and lactoferrin exhibited dynamic correlations with iron variables (p < 0.05), reflecting competition between erythropoiesis and immune function for iron. The structure of the Granger causality network places transferrin in a central role, highlighting iron metabolism as one key regulator of these adaptations. Normobaric hypoxia training induces systemic physiological changes involving hematological, iron, and immune systems. Controlled hypoxic conditions enable detailed exploration of these interactions, providing insights into optimizing altitude training strategies for endurance performance enhancement.

Although anemia is a common systemic toxicological manifestation of zinc product overload, the underlying mechanisms remain elusive. Therefore, we explored the mechanisms underlying the anemia caused by exposure to zinc oxide nanoparticles (ZnO NPs), which are a widely utilized Zn product. We observed that ZnO NP-exposed mice developed evident anemia due to disrupted spleen iron metabolism. Since spleen iron metabolism relies on macrophages, we further investigated how ZnO NP exposure affected macrophage function. Results indicated that ZnO NP exposure triggered macrophage metabolic reprogramming to facilitate erythrophagocytosis and blunted the response of iron exporter ferroportin to enhanced erythrophagocytosis, thereby causing iron retention and ultimately impeding macrophage iron recycling. Mechanistically, Zn2+ released from ZnO NPs occupied the cluster-binding cysteines of iron-sulfur proteins, regulating glucose metabolism and ferroportin expression to suppress their activity, thereby inducing metabolic reprogramming and suppressing iron export. Our research unveils a category of nanobio interactions underlying ZnO NPs biotoxicity.

Iron responsive element (IREs) mRNA and iron regulatory proteins (IRPs) regulate iron homeostasis. 5'-untranslated region motifs of APP IREs fold into RNA stem loops bind to IRP to control translation. Through the 5'-UTR APP IREs, iron overload accelerated the translation of the Alzheimer's amyloid precursor protein (APP). The protein synthesis activator eIF4F and the protein synthesis repressor IRP1 are the two types of proteins that IREs bind. Iron regulates the competitive binding of eIF4F and IRP1 to IRE. Iron causes the IRE and eIF4F to associate with one other, causing the dissociation of IRPs and altered translation. In order to control IRE-modulated expression of APP, messenger RNAs are becoming attractive targets for the development of small molecule therapeutics. Many mRNA interference strategies target the 2-D RNA structure, but messenger RNAs like rRNAs and tRNAs can fold into complicated, three-dimensional structures that add another level of complexity. IREs family is one of the few known 3-D mRNA regulatory elements. In this review, I present IREs structural and functional characteristics. For iron metabolism, the mRNAs encoding the proteins are controlled by this family of similar base sequences. Iron has a similar way of controlling the expression of Alzheimer's APP as ferritin IRE RNA in their 5ÚTR. Further, iron mis regulation by IRPs can be investigated and contrasted using measurements of expression levels of APP, amyloid-β and tau formation. Accordingly, IRE-modulated APP expression in Alzheimer's disease has great therapeutic potential through targeting mRNA structures.

Colorectal cancer (CRC) development is influenced by both iron and gut microbiota composition. While iron supplementation is routinely used to manage anemia in CRC patients, it may also impact gut microbiota and promote tumorigenesis. In this study, we investigated the impact of initial gut microbiota composition on iron-promoted tumorigenesis. We performed fecal microbiota transplantation (FMT) in ApcMin/+ mice using samples from healthy controls, CRC patients, and mice, followed by exposure to iron sufficient or iron excess diets.

We found that iron supplementation promoted CRC and resulted in distinct gut microbiota changes in ApcMin/+ mice receiving FMT from CRC patients (FMT-CRC), but not from healthy controls or mice. Oral treatment with identified bacterial strains, namely Faecalibaculum rodentium, Holdemanella biformis, Bifidobacterium pseudolongum, and Alistipes inops, protected FMT-CRC mice against iron-promoted tumorigenesis.

Our findings suggest that microbiota-targeted interventions may mitigate tumorigenic effects of iron supplementation in anemic patients with CRC.

Iron homeostasis plays an important role in maintaining cellular homeostasis; however, excessive iron can promote the production of reactive oxygen species (ROS). Ferroptosis is iron-dependent programmed cell death that is characterized by excessive iron accumulation, elevated lipid peroxides, and the overproduction of ROS. The maintenance of iron homeostasis is contingent upon the activity of the transferrin receptor (TfR), ferritin (Ft), and ferroportin (FPn). In the retina, iron accumulation and lipid peroxidation can contribute to the development of age-related macular degeneration (AMD). This phenomenon can be explained by the occurrence of the Fenton reaction, in which the interaction between divalent iron and hydrogen peroxide leads to the generation of highly reactive hydroxyl radicals. The hydroxyl radicals exhibit a propensity to attack proteins, lipids, nucleic acids, and carbohydrates, thereby instigating oxidative damage and promoting lipid peroxidation. Ultimately, these processes culminate in cell death and retinal degeneration. In this context, a comprehensive understanding of the exact mechanisms underlying ferroptosis may hold significant importance for developing therapeutic interventions. This review summarizes recent findings on iron metabolism, cellular ferroptosis, and lipid metabolism in the aging retina. We also introduce developments in the therapeutic strategies using iron chelating agents. Further refinements of these knowledges would deepen our comprehension of the pathophysiology of AMD and advance the clinical management of degenerative retinopathy. A comprehensive search strategy was employed to identify relevant studies on the role of ferroptosis in AMD. We performed systematic searches of the PubMed and Web of Science electronic databases from inception to the current date. The keywords used in the search included "ferroptosis", "AMD", "age-related macular degeneration", "iron metabolism", "oxidative stress", and "ferroptosis pathways". Peer-reviewed articles, including original research, reviews, meta-analyses, and clinical studies, were included in this paper, with a focus on the molecular mechanisms of ferroptosis in AMDs. Studies not directly related to ferroptosis, iron metabolism, or oxidative stress in the context of AMD were excluded. Furthermore, articles that lacked sufficient data or were not peer-reviewed (e.g., conference abstracts, editorials, or opinion pieces) were not considered.

Copy number variants (CNVs) are an important class of genomic variation known to be important for human physiology and diseases. Here we present genome-wide metabolomic signatures for CNVs in two Finnish cohorts-The Northern Finland Birth Cohort 1966 (NFBC 1966) and NFBC 1986. We have analysed and reported CNVs in over 9,300 individuals and characterised their dosage effect (CNV-metabolomic QTL) on 228 plasma lipoproteins and metabolites. We have reported reference (normal physiology) metabolomic signatures for up to ~ 2.6 million COVID-19 GWAS results from the National Institutes of Health (NIH) GRASP database, including for outcomes related to COVID-19 death, severity, and hospitalisation. Furthermore, by analysing two exemplar genes for COVID-19 severity namely LZTFL1 and OAS1, we have reported here two additional candidate genes for COVID-19 severity biology, (1) NFIX, a gene related to viral (adenovirus) replication and hematopoietic stem cells and (2) ACSL1, a known candidate gene for sepsis and bacterial inflammation. Based on our results and current literature we hypothesise that (1) charge imbalance across the cellular membrane between cations (Fe2+, Mg2+ etc.) and anions (e.g. ROS, hydroxide ion from cellular Fenton reactions, superoxide etc.), (2) iron trafficking within and between different cell types e.g., macrophages and (3) systemic oxidative stress response (e.g. lipid peroxidation mediated inflammation), together could be of relevance in severe COVID-19 cases. To conclude, our unique atlas of univariate and multivariate metabolomic signatures for CNVs (~ 7.2 million signatures) with deep annotations of various multi-omics data sets provide an important reference knowledge base for human metabolism and diseases.

Transmembrane-receptor-mediated recognition is fundamental to signaling and nutrient transport in diverse biological systems. While traditional models involve direct ligand-receptor binding, emerging evidence supports a relay model, in which substrate-binding proteins transfer ligands to receptors or form cooperative receptor complexes. This mechanism enhances the specificity and versatility of the ligand-receptor network.

The pathophysiology of intracerebral hemorrhage (ICH) is complex and can cause variable degrees of cell death. Recently, ferroptosis, an emerging cell death mechanism, has garnered significant attention in cerebral hemorrhage disorder. This study aimed to examine iron mortality after cerebral hemorrhage and current targets for potential therapeutic interventions. We specifically focused on iron metabolism abnormalities, lipid peroxidation, and related neuroinflammation and introduced molecular mechanisms, including transcription factors, to gain a better understanding of the underlying mechanisms of ferroptosis and investigate possible therapeutic options for ICH.

Cancer is a global health challenge, and its development is closely linked to iron metabolism. Cancer cells have an increased demand for this element, which promotes their proliferation, invasion, and metastasis. Excess iron catalyzes the formation of reactive oxygen species (ROS), which can both induce ferroptosis and initiate oncogenic signaling pathways. The deregulation of iron metabolism in cancer patients leads to anemia or toxic iron overload and also affects the gut microbiota. Lactoferrin (LF), a glycoprotein with strong iron chelating properties, can regulate its availability to cancer cells, thereby limiting their growth and progression. By chelating free Fe ions, LF reduces oxidative stress and inhibits the mechanisms that promote carcinogenesis. Additionally, it exhibits immunomodulatory and anti-inflammatory effects and may enhance the body's anti-tumor response. This review analyses the mechanisms of action of lactoferrin in the context of cancer, with a particular focus on its chelating, antioxidant, and immunomodulatory properties. The multidirectional effects of LF make it a promising component of preventive and therapeutic strategies, requiring further clinical studies.

Hyperoxia therapy is a critical clinical intervention for both acute and chronic illnesses. However, prolonged exposure to high-concentration oxygen can cause lung injury. The mechanisms of hyperoxic lung injury (HLI) remain incompletely understood, and current treatment options are limited. Improving the safety of hyperoxia therapy has thus become an urgent priority. Ferroptosis, a novel form of regulated cell death characterized by iron accumulation and excessive lipid peroxidation, has been implicated in the pathogenesis of HLI, including diffuse alveolar damage, vascular endothelial injury, and bronchopulmonary dysplasia. In this review, we analyze the latest findings on ferroptosis and therapeutic strategies for HLI. Our aim is to provide new insights for the treatment of HLI and to facilitate the translation of these findings from bench to bedside.

Acute erythroid leukemia (AEL) is a rare acute myeloid leukemia (AML) subtype that is highly aggressive and is associated with a poor prognosis. Notably, the blockage of erythroid differentiation represents a significant factor in the pathogenesis of erythroleukemia. Prior studies indicated that miR-218 inhibited the erythroid differentiation in a chronic myeloid leukemia (CML)-derived erythroleukemia cell line K562. However, functions of miR-218 in primary AEL remains to be elucidated. To address this gap, functions of miR-218 in HEL cells were evaluated through cell differentiation, cell proliferation, colony formation, cell cycle and cell apoptosis experiments. Subsequently, the targeted downstream genes of miR-218 were identified by the transcriptome sequencing and bioinformatic research, of which demonstrated by the dual-luciferase reporter experiment. Finally, the underlying mechanism of miR-218 in leukemogenesis was identified by enrichment analysis and was validated by western blot (WB) assays. Intriguingly, enhanced miR-218 showed no effect on the erythroid differentiation in HEL cells by determination of the expression of erythroid markers including GATA1, KLF1, TFRC and GYPA. However, miR-218 overexpression in HEL cells presented a markedly anti-proliferative and pro-apoptotic effects, inhibited colony formation and G0/G1 arrest. Transcriptome sequencing and bioinformatics analysis revealed that CTNND2 as the candidate gene of miR-218 within its 3'-untranslated region (3'-UTR) could be bonded by it. Reduced expression level of CTNND2 was further demonstrated by quantitative-PCR and WB after miR-218 overexpression in HEL cells. Furthermore, the luciferase report assay revealed that the CTNND2 production was reduced with its 3'-UTR region was bonded by miR-218. In addition, MAPK signaling pathway was identified and validated as the potential functional pathway involved in leukemogenesis caused by miR-218 overexpression in HEL cells. In summary, miR-218 exhibits anti-proliferative and pro-apoptotic functions by targeting CTNND2 and modulating MAPK signaling in HEL cells, yet it has no impact on the erythroid differentiation process.

Mitochondrial functionality and cellular iron homeostasis are closely intertwined. Mitochondria are biosynthetic hubs for essential iron cofactors such as iron-sulfur (Fe-S) clusters and heme. These cofactors, in turn, enable key mitochondrial pathways, such as energy and metabolite production. Mishandling of mitochondrial iron is associated with a spectrum of human pathologies ranging from rare genetic disorders to common conditions. Here, we review mitochondrial iron utilization and its intersection with disease.

Iron is an essential micronutrient for abounding physiological processes in the body, and its deficiency can be caused by various factors, such as low iron intake due to economic difficulties or loss of appetite, decreased iron absorption due to gastrointestinal issues, or increased iron loss due to hemorrhages or proteinuria. Iron deficiency is a prevalent issue among heart failure (HF) patients and is a significant contributor to anemia, affecting 30-50% of patients regardless of their gender, ethnicity, or left ventricular ejection fraction. Individuals with HF have high levels of pro-inflammatory cytokines, which can inhibit erythropoiesis by degrading the membrane iron exporter ferroportin, mediated by an increased release of hepcidin. In addition, elevated sympathetic and renin-angiotensin-aldosterone system activity retains salt and water, resulting in high cardiac output HF in people with normal left ventricular function. This review provides an overview of iron deficiency and HF.

Deferoxamine (DFO) is an FDA-approved naturally occurring iron chelator commonly used to treat transfusion-induced iron overload. The abundant and flexible hydroxamic acid groups in DFO enable exceptional iron binding capacity and high protein binding via hydrogen bonding interactions. However, the applications of DFO to sequester intracellular iron and to deliver proteins inside cells are limited due to poor membrane-permeability. Herein, the fabrication of a dynamic DFO polymer is proposed to achieve robust intracellular protein delivery and efficient mitochondrial iron depletion. Specifically, DFO is grafted onto a polycatechol scaffold via dynamic catechol-boronate chemistry. The obtained DFO polymer shows robust protein binding capacity, and the formed protein complexes show high resistance toward serum proteins. It effectively delivers various cargo proteins into cytosol of treated cells with maintained bioactivity. In addition, the polymer delivers DFO inside cells, and the released DFO efficiently depletes mitochondrial iron, which significantly inhibits mitochondrial oxidative phosphorylation and glycolysis. Remarkable synergistic cytotoxic effects are achieved when the DFO polymer is loaded with toxic proteins. This study provides a general strategy for facile preparation of bioactive polymer toward robust protein delivery, and the designed polymer can be a promising carrier for the delivery of protein therapeutics to treat cancer.

Iron accumulation and mitochondrial dysfunction in astroglia are reported in Parkinson's disease (PD). Astroglia control iron availability in neurons in which dopamine (DA) synthesis is affected in PD. Despite their intimate relationship the role of DA in astroglial iron homeostasis is limited. Here we show that DA degrades iron storage protein ferritin in astroglial cells involving lysosomal proteolysis. Lysosomal ferritinophagy is mainly associated with macroautophagy; however, we revealed the involvement of chaperone-mediated autophagy (CMA) in DA-induced ferritin degradation. In CMA, cytosolic proteins containing a specific pentapeptide motif bind with HSC70 to be transported to lysosome mediated by LAMP2A. We identified the conserved pentapeptide motif in ferritin-H (Ft-H), mutations of which resulted loss of its interaction with HSC70. Pharmacological inhibitors of HSC70 or LAMP2/2A knockdown blocks DA-induced Ft-H degradation. DA also induces cytosolic cargo NCOA4 for ferritinophagy. We further reveal that DA promotes cathepsin B to lysis ferritin within the lysosome. Inhibitor of cathepsin B, knocking down of LAMP2, or HSC70 inhibitor attenuate DA-induced elevated mitochondrial iron level. Our results establish a direct role of DA on astroglial iron homeostasis and novel involvement of CMA in ferritin degradation in response to a biological stimulus. These results also may help in better understanding iron dyshomeostasis and mitochondrial dysfunction reported in PD.

The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.

Mitochondrial tRNA taurine modifications mediated by mitochondrial tRNA translation optimization 1 (Mto1) is essential for the mitochondrial protein translation. Mto1 deficiency was shown to induce proteostress in embryonic stem cells. A recent finding that a patient with MTO1 gene mutation showed severe anemia led us to hypothesize that Mto1 dysfunctions may result in defective erythropoiesis. Hematopoietic-specific Mto1 conditional knockout (cKO) mice were embryonic lethal and showed niche-independent defect in erythroblast proliferation and terminal differentiation. Mechanistically, mitochondrial oxidative phosphorylation complexes were severely impaired in the Mto1 cKO fetal liver, and this was followed by cytosolic iron accumulation. Overloaded cytosolic iron promoted heme biosynthesis, which induced an unfolded protein response (UPR) in Mto1 cKO erythroblasts. An iron chelator or UPR inhibitor rescued erythroid terminal differentiation in the Mto1 cKO fetal liver in vitro. This mitochondrial regulation of iron homeostasis revealed the indispensable role of mitochondrial tRNA modification in fetal hematopoiesis.

Iron is one of the crucial elements for CNS development and function and its deficiency (ID) is the most common worldwide nutrient deficit in the world. Iron deficiency anemia (IDA) in pregnant women and infants is a worldwide health problem due to its high prevalence and its irreversible long-lasting effects on brain development. Even with iron supplementation, IDA during pregnancy and/or breastfeeding can result in irreversible cognitive, motor, and behavioral impairments. The neurovascular unit (NVU) plays an important role in iron transport within the CNS as well as in the blood brain-barrier (BBB) formation and maturation, vasculogenesis/angiogenesis, neurovascular coupling and metabolic waste clearance. In animal models of IDA, significant changes have been observed at the capillary level, including alterations in iron transport, vasculogenesis, astrocyte endfeet, and pericytes. Despite these findings, the role of the NVU in IDA remains poorly understood. This review summarizes the potential effects of ID/IDA on brain development, myelination and neuronal function and discusses the role of NVU cells in iron metabolism, BBB, vasculogenesis/angiogenesis, neurovascular coupling and metabolic waste clearance. Furthermore, it emphasizes the need to view the NVU as a whole and as a potential target for ID/IDA. However, it remains unclear to what extent NVU alterations contribute to neuronal dysfunction, myelination abnormalities, and synaptic disturbances described in IDA.

In this paper, lanthanum and cerium co-doped carbon quantum dots (LaCe-CQDs) was firstly synthesized by one step hydrothermal method. The obtained LaCe-CQDs shown sable fluorescence properties with pH values from 3 to 9 and after 4 weeks of storage. The average particle size of LaCe-CQDs, with excitation and emission wavelengths of 350 nm and 446 nm, is 3.27 ± 0.12 nm. Selective analysis of various metal ions revealed the sensitivity of LaCe-CQDs towards Fe3+ ions. Within the 0-60 μM, the fluorescence intensity exhibits a strong linear correlation with the concentration of Fe3+. The limit of detection (LOD) was determined to be 0.753 μM. Additionally, the accuracy of LaCe-CQDs were demonstrated in natural water samples. Therefore, LaCe-CQDs are a promising sensor for Fe3+ detection.

Cardiovascular diseases represent the principal cause of death and comorbidity among people with diabetes. Ferroptosis, an iron-dependent non-apoptotic regulated cellular death characterized by lipid peroxidation, is involved in the pathogenesis of diabetic cardiovascular diseases. The susceptibility to ferroptosis in diabetic hearts is possibly related to myocardial iron accumulation, abnormal lipid metabolism and excess oxidative stress under hyperglycemia conditions. Accumulating evidence suggests ferroptosis can be the therapeutic target for diabetic cardiovascular diseases. This review summarizes ferroptosis-related mechanisms in the pathogenesis of diabetic cardiovascular diseases and novel therapeutic choices targeting ferroptosis-related pathways. Further study on ferroptosis-mediated cardiac injury can enhance our understanding of the pathophysiology of diabetic cardiovascular diseases and provide more potential therapeutic choices.

Iron overload disease is characterized by the excessive accumulation of iron in the body. To better alleviate iron overload, there is an urgent need for safe and effective small molecule compounds. Rubiadin, the active ingredient derived from the Chinese herb Prismatomeris tetrandra, possesses notable anti-inflammatory and hepatoprotective properties. Nevertheless, its impact on iron metabolism remains largely unexplored. To determine the role of rubiadin on iron metabolism, Western blot analysis, real-time PCR analysis, and the measurement of serum iron were performed. Herein, we discovered that rubiadin significantly downregulated the expression of transferrin receptor 1, ferroportin 1, and ferritin light chain in ferric-ammonium-citrate-treated or -untreated HepG2 cells. Moreover, intraperitoneal administration of rubiadin remarkably decreased serum iron and duodenal iron content and upregulated expression of hepcidin mRNA in the livers of high-iron-fed mice. Mechanistically, bone morphogenetic protein 6 (BMP6) inhibitor LDN-193189 completely reversed the hepcidin upregulation and suppressor of mother against decapentaplegic 1/5/9 (SMAD1/5/9) phosphorylation induced by rubiadin. These results suggested that rubiadin increased hepcidin expression through the BMP6/SMAD1/5/9-signaling pathway. Collectively, our findings uncover a crucial mechanism through which rubiadin modulates iron metabolism and highlight it as a potential natural compound for alleviating iron-overload-related diseases.

Tumor cells reshape iron and lipid metabolism for their rapid proliferation. However, how tumor cells coordinate the interplay between tumor cell-specific iron homeostasis and lipid metabolism reprogramming to counteract energy shortages remains unclear. Here, we demonstrated that glucose deprivation in hepatocellular carcinoma (HCC) cells induced AMPK-dependent Transferrin S685 phosphorylation, which exposed Transferrin nuclear localization signal (NLS) for binding to importin α7 and subsequent nuclear translocation. Nucleus-translocated Transferrin interacts with PPARα and enhance its protein stability to increase fatty acid oxidation (FAO) upon glucose deprivation. Mechanistically, PPARα-associated Transferrin upregulates iron-dependent PHD2-mediated PPARα P87 hydroxylation and subsequently disrupts the binding of MDM2 to PPARα, therefore inhibiting MDM2-mediated PPARα ubiquitination and degradation. Reconstitution of Transferrin S685A and NLS mutation or knock-in expression of PPARα P87A inhibited PPARα-mediated FAO upon energy stress, enhanced HCC cell apoptosis, and impeded liver tumor growth in mice. Importantly, combined treatment with Transferrin pS685 blocking peptide suppressing AMPK-Transferrin-PPARα axis could synergize with a well-established AMPK activator Metformin to inhibit tumor growth. Additionally, Transferrin pS685-mediated PPARα P87 hydroxylation is positively correlated with PPARα expression levels in human HCC specimens and poor patient prognosis. These findings revealed a mechanism by which Transferrin can sense energy stress to promote the hydroxylation and protein stability of PPARα through iron-dependent activation of PHD2 and underscore the moonlighting function of Transferrin in lipid catabolism and liver tumor development.

Cadmium (Cd2+) is a heavy metal that is a major hazardous environmental contaminant, ubiquitously present in the environment. Cd2+ exposure has been closely associated with an increased prevalence and severity of neurological and cardiovascular diseases (CVD). The blood-brain barrier (BBB) plays a crucial role in protecting the brain from external environmental factors. Mitochondria play an important role in maintaining the barrier function of brain endothelial cells by regulating energy metabolism and redox homeostasis. In this study, we aimed to assess the cytotoxic effects of Cd2+ on the integrity and function of brain endothelial cells. After 24 h of exposure, Cd2+ reduced cell survival, tight junction protein expression, and trans-endothelial electrical resistance (TEER) in bEnd.3 cells suggest a potential BBB integrity disruption by Cd2+ exposure. To clarify the underlying mechanism, we further investigated the role of mitochondria in iron overload-mediated cell death following Cd2+ exposure. Cd2+ induced a substantial reduction in mitochondrial basal respiration and ATP production in brain endothelial cells, suggesting mitochondrial dysfunction. In addition, Cd2+ exposure led to impaired autophagy, elevated iron levels, and increased lipid peroxidation, indicating the initiation of ferroptosis, a form of cell death triggered by iron. In summary, our research suggests that Cd2+ exposure can disrupt BBB function by causing mitochondrial dysfunction and disrupting iron homeostasis.

Brain iron (Fe) dyshomeostasis is implicated in neurodegenerative diseases. Genome-wide association studies (GWAS) have identified plausible loci correlated with peripheral levels of Fe. Systemic organs and the brain share several Fe regulatory proteins but there likely exist different homeostatic pathways. We performed the first GWAS of inductively coupled plasma mass spectrometry measures of postmortem brain Fe from 635 Rush Memory and Aging Project (MAP) participants. Sixteen single nucleotide polymorphisms (SNPs) associated with Fe in at least one of four brain regions were measured (p < 5 × 10-8). Promising SNPs (p < 5 × 10-6) were followed up for replication in published GWAS of blood, spleen, and brain imaging Fe traits and mapped to candidate genes for targeted cortical transcriptomic and epigenetic analysis of postmortem Fe in MAP. Results for SNPs previously associated with other Fe traits were also examined. Ninety-eight SNPs associated with postmortem brain Fe were at least nominally (p < 0.05) associated with one or more related Fe traits. Most novel loci identified had no direct links to Fe regulatory pathways but rather endoplasmic reticulum-Golgi trafficking (SORL1, SORCS2, MARCH1, CLTC), heparan sulfate (HS3ST4, HS3ST1), and coenzyme A (SLC5A6, PANK3); supported by nearest gene function and omic analyses. We replicated (p < 0.05) several previously published Fe loci mapping to candidate genes in cellular and systemic Fe regulation. Finally, novel loci (BMAL, COQ5, SLC25A11) and replication of prior loci (PINK1, PPIF, LONP1) lend support to the role of circadian rhythms and mitochondria function in Fe regulation more generally. In summary, we provide support for novel loci linked to pathways that may have greater relevance to brain Fe accumulation; some of which are implicated in neurodegeneration. However, replication of a subset of prior loci for blood Fe suggests that genetic determinants or biological pathways underlying Fe accumulation in the brain are not completely distinct from those of Fe circulating in the periphery.

Iron deficiency (ID) is a critical public health issue globally and the most prevalent cause of anemia. Iron deficiency anemia (IDA) affects approximately 1.2 billion individuals worldwide, and it is estimated that non-anemic iron deficiency (NAID) is at least twice as common as IDA. Yet, there is still uncertainty about how to diagnose it in clinical practice. The serum ferritin (SF) threshold of <15 ng/mL proposed by the World Health Organization (WHO) has been questioned over the last decade. The current SF thresholds are inappropriately low, and, therefore, a large portion of the population at the most significant risk of ID remain undiagnosed and untreated. The correlation between SF, hepcidin, and the physiological upregulation of iron absorption in healthy adults suggests that SF of <50 ng/mL indicates a more precise threshold for diagnosing ID in adults. Therefore, adopting the SF threshold <50 ng/mL would break up the perpetuation of an inequitable cycle of disadvantage for ID individuals, especially among women.

The success of hematopoietic transplantation for hemoglobinopathies and hematological malignancies has been accompanied by the new challenge of how to identify, risk stratify, and treat iron overload and toxicity before and after transplantation. Substantial progress has been made in our understanding of iron metabolism and the pathophysiology of iron overload, making us aware that not only the total amount of iron in the body is important but also the effect of toxic iron species and duration of exposure are equally relevant. Challenges still remain in how to assess cellular and tissue damage and define the mechanism that may detrimentally affect the outcome of hematopoietic transplantation. In this article, I discuss the impact of iron toxicity in relation to the different phases of hematopoietic transplantation, before, during, and after, for both malignant and nonmalignant diseases. Different clinical scenarios and possibilities for therapeutic intervention are also outlined and discussed.

Ferroptosis, a type of programmed cell death, represents a distinct paradigm in cell biology. It is characterized by the iron-dependent accumulation of reactive oxygen species, which induce lipid peroxidation (LPO), and is orchestrated by the interplay between iron, lipid peroxides, and glutathione. In this review, we emphasize the frequently overlooked role of iron in LPO beyond the classical iron-driven Fenton reaction in several crucial processes that regulate cellular iron homeostasis, including iron intake and export as well as ferritinophagy, and the emerging roles of endoplasmic reticulum-resident flavoprotein oxidoreductases, especially P450 oxidoreductases, in modulating LPO. We summarize how various types of fatty acids (FAs), including saturated, monounsaturated, and polyunsaturated FAs, differentially influence ferroptosis when incorporated into phospholipids. Furthermore, we highlight the therapeutic potential of targeting LPO to mitigate ferroptosis and discuss the regulatory mechanisms of endogenous lipophilic radical-trapping antioxidants that confer resistance to ferroptosis, shedding light on therapeutic avenues for ferroptosis-associated diseases.

Ferritin is found in all cells of the body, serving as a reservoir of iron and protecting against damage to the molecules that make up cellular structures. It has emerged as a biomarker not only for iron-related disorders but also for inflammatory diseases and conditions in which inflammation plays a key role, including cancer, neurodegeneration, and infection. Oxidative stress, which can cause cellular damage, is induced by reactive oxygen species generated during the Fenton reaction, activating signaling pathways associated with tumor growth and proliferation. This review primarily emphasizes basic studies on the identification and function of ferritin, its essential role in iron metabolism, its involvement in inflammatory diseases, and its potential as an important prognostic factor and biomarker for cancer detection.

RNA-binding proteins (RBPs) are critical regulators of mRNAs controlling all processes such as RNA transcription, transport, localization, translation, mRNA:ncRNA interactions, and decay. Cellular differentiation is driven by tissue-specific and/or tissue-preferred expression of proteins needed for the optimal function of mature cells, tissues and organs. Lens fiber cell differentiation is marked by high levels of expression of crystallin genes encoding critical proteins for lens transparency and light refraction. Herein we performed proteomic and transcriptomic analyses of RBPs in differentiating mouse lenses to identify the most abundant RBPs and establish dynamic changes of their expression in differentiating lens. Expression analyses include highly abundant RBPs, including Carhsp1, Igf2bp1/ZBP1, Ybx1, Pabpc1, Ddx39, and Rbm38. Binding sites of Carhsp1, Ybx1, and Igf2bp1/ZBP1 were predicted in various crystallin and β-actin mRNAs. Immunoprecipitations using antibodies against Carhsp1, Igf2bp1/ZBP1, and Ybx1 confirmed their interactions with αA-, αB-, and γA-crystallin mRNAs. A combination of single molecule RNA FISH (smFISH) and immunofluorescence was used to probe in vivo interactions of these RBPs with αA-, αB-crystallin, and β-actin mRNAs in cytoplasm and nucleoplasm of cultured mouse lens epithelial cells. Together, these results open new avenues to perform comprehensive genetic, cell, and molecular biology studies of individual RBPs in the lens.

Breast cancer is the most commonly diagnosed cancer worldwide. Metal metabolism is pivotal for regulating cell fate and drug sensitivity in breast cancer. Iron and copper are essential metal ions critical for maintaining cellular function. The accumulation of iron and copper ions triggers distinct cell death pathways, known as ferroptosis and cuproptosis, respectively. Ferroptosis is characterized by iron-dependent lipid peroxidation, while cuproptosis involves copper-induced oxidative stress. They are increasingly recognized as promising targets for the development of anticancer drugs. Recently, compelling evidence demonstrated that the interplay between ferroptosis and cuproptosis plays a crucial role in regulating breast cancer progression. This review elucidates the converging pathways of ferroptosis and cuproptosis in breast cancer. Moreover, we examined the value of genes associated with ferroptosis and cuproptosis in the clinical diagnosis and treatment of breast cancer, mainly outlining the potential for a co-targeting approach. Lastly, we delve into the current challenges and limitations of this strategy. In general, this review offers an overview of the interaction between ferroptosis and cuproptosis in breast cancer, offering valuable perspectives for further research and clinical treatment.

Organisms as well as pathogens require several transition metals including iron, copper, zinc, manganese, nickel and cobalt, for genetic replication and other cellular functions. Of these, iron is vital and plays a key role in DNA replication, transcription, synthesis of cofactors and other essential enzymes. During infection, iron deprivation, particularly sequestration thereof, represents a unique response against pathogen attack. The host sequesters ferrous (Fe2+) and ferric (Fe3+) iron via lactoferrin binding at mucosal surfaces, transferrin in blood and tissue and ferritin in blood and cytoplasm. Despite this protective mechanism, pathogens can be resilient in obtaining iron. For example, hemolytic protozoan parasites can obtain iron from heme by rupturing red blood cells. Furthermore, earlier pathogens, driven from active to inactive infections by iron deprivation, could now acquire sufficient iron to enable reactivation resulting in chronic inflammation, oxidative stress to organs and/or circulatory hypertension potentially leading to death. This review discusses the impact of hemolytic protozoan parasite infection in reactivation of latent iron-deprived pathogen infections thus explaining two puzzling pregnancy disorders, pre-eclampsia (PE) and eclampsia. The unknown causations of both disorders have created centuries of confusion and killed millions of women worldwide. Furthermore, reduction-oxidation reactions with iron promote additional oxidative stress damage to vital organs, particularly the kidneys, a common symptom in PE and eclampsia.

Although traditionally regarded as an impediment, the protein corona can facilitate the advancement of targeted drug delivery systems. This study presents an innovative approach for targeting acute myeloid leukemia (AML) using nanoparticles with agglutinated protein (NAPs). Agglutinated transferrin and C3b in NAPs selectively bind to CD71 and CD11b, receptors that are overexpressed on myeloid leukemic cells compared to nonmalignant cells. In vitro, NAPs achieved a 73.9% doxorubicin (DOX) uptake in leukemic cells, compared to 6.19% for the free drug, while significantly reducing off-target accumulation in normal cells from 42.9% to 5.76%. In vivo, the distribution of NAPs correlated to the organ infiltration pattern of leukemic cells. NAPs demonstrated antileukemic activity in both in vitro and in vivo NSG mouse models, inducing cell death via apoptosis and ferroptosis. In conclusion, NAP-mediated targeted drug delivery represents a promising therapeutic strategy for AML, enhancing treatment efficacy and minimizing off-target effects.