Disruption Of Iron Homeostasis Research Articles

Micronutrient Balance Related to Neural Tube Defects and Prevention

Neural tube defects (NTDs) are a common congenital disorder resulting from failed neural tube formation, the precursor of the brain and spinal cord. The complex etiology of NTDs involve both genetic and environmental factors, thus investigating gene‐environment interactions is critical to understanding how NTDs occur or how NTDs may be prevented. For example, iron deficiency is among the most prevalent micronutrient deficiencies in pregnancy and there is evidence that iron deficiency can increase the risk of NTDs. Folic acid (FA) fortification in grain was implemented in the US in 1998 and now in many countries for the purpose of prevention of neural tube defects (NTDs). In 2017, the US Preventive Services Task Force further recommended the consumption of FA‐containing multivitamin/minerals (MVM) for women of childbearing age. Despite the great benefit of FA on NTD prevention, NTDs remain a serious risk.Our studies focus on mouse models of NTDs and I will discuss two projects. First, the benefits of MVM supplementation are emphasized, but a comparison between MVM supplementation and FA alone on neural tube closure and organ development has not been evaluated, particularly in the context of genetic mutations that lead to NTDs. Using a set of NTD models we have compared MMV to FA supplementation. MVM supplementation shows better improvement than FA alone in the penetrance of spinal and cranial NTDs. We are also using human iPSCs to generate organoids that assume a shape similar to the human spinal neural tube, and display neural tube characteristics, for example apical constriction and interkinetic nuclear migration. Subjecting the organoids to various molecular perturbations, such as Rho‐kinase inhibitor‐induced defects in apical constriction, we have found that both MVM and FA largely prevents this molecular deficit. The goal is to use the mouse NTD model and organoid system to better understand how FA/MVM act to prevent NTDs.Second, we are striving to move beyond the relatively non‐specific recommendations of FA/MVM supplementation to more personalized therapies that take into account the molecular underpinning of the NTD. For example, Iron homeostasis is not only controlled by the concentration of iron in diet, but by proteins responsible for its cellular uptake and metabolism. Sorting nexin 3 (Snx3) is known to regulate recycling of the transferrin receptor (TFRC), a mechanism necessary for cellular uptake of iron, and when Snx3 is knocked out in mice, embryos develop cranial NTDs. We hypothesize that in Snx3 mutants, mistrafficking of TFRC results in disrupted iron homeostasis which contributes to the failure of NT closure. Our current studies are evaluating whether intracellular iron levels are altered in Snx3 mutants and whether maternal diets supplemented with iron can prevent NTDs in the Snx3 background. The hope is that by taking into account the biological process that is disrupted, more tailored therapies can be envisioned to better prevent NTDs.

Apigenin ameliorates di(2-ethylhexyl) phthalate-induced ferroptosis: The activation of glutathione peroxidase 4 and suppression of iron intake

Di(2-ethylhexyl) phthalate (DEHP) is a widely artificial persistent organic pollutant, the contamination of which infiltrates daily human life from many aspects, imperceptibly causing damage to multiple organs in the body, including the liver. Apigenin (APG) is widely distributed in vegetables and fruits and can relieve or prevent the injuries caused by exogenous chemicals through various pharmacological effects, such as antioxidant effects. To investigate the mechanism of DEHP-induced liver injury and the antagonistic effects of APG, we treated AML12 cells with 1 mM DEHP and/or APG. Ultrastructural morphology analysis indicated that DEHP induced typical ferroptosis-like damage. In addition, we found that DEHP exposure induced ferroptosis by enhancing reactive oxygen species (ROS) levels, disrupting iron homeostasis and lipid peroxidation, and regulating the expression of ferroptosis-related genes. Notably, supplementation with APG significantly inhibited these abnormal changes, and molecular docking further showed evidence of the activating effects of APG ligand on glutathione peroxidase 4 (GPX4). These results demonstrated that the protective effects of APG on DEHP-induced ferroptosis were achieved by activating GPX4 and suppressing intracellular iron accumulation. This information not only adds to DEHP toxicological data but also provides a basis for the practical application of APG.

Iron Homeostasis in the CNS: An Overview of the Pathological Consequences of Iron Metabolism Disruption.

Iron homeostasis disruption has increasingly been implicated in various neurological disorders. In this review, we present an overview of our current understanding of iron metabolism in the central nervous system. We examine the consequences of both iron accumulation and deficiency in various disease contexts including neurodegenerative, neurodevelopmental, and neuropsychological disorders. The history of animal models of iron metabolism misregulation is also discussed followed by a comparison of three patients with a newly discovered neurodegenerative disorder caused by mutations in iron regulatory protein 2.

Disruption of Iron Homeostasis and Mitochondrial Metabolism Are Promising Targets to Inhibit Candida auris.

ABSTRACTFungal infections are a global threat, but treatments are limited due to a paucity in antifungal drug targets and the emergence of drug-resistant fungi such as Candida auris. Metabolic adaptations enable microbial growth in nutrient-scarce host niches, and they further control immune responses to pathogens, thereby offering opportunities for therapeutic targeting. Because it is a relatively new pathogen, little is known about the metabolic requirements for C. auris growth and its adaptations to counter host defenses. Here, we establish that triggering metabolic dysfunction is a promising strategy against C. auris. Treatment with pyrvinium pamoate (PP) induced metabolic reprogramming and mitochondrial dysfunction evident in disrupted mitochondrial morphology and reduced tricarboxylic acid (TCA) cycle enzyme activity. PP also induced changes consistent with disrupted iron homeostasis. Nutrient supplementation experiments support the proposition that PP-induced metabolic dysfunction is driven by disrupted iron homeostasis, which compromises carbon and lipid metabolism and mitochondria. PP inhibited C. auris replication in macrophages, which is a relevant host niche for this yeast pathogen. We propose that PP causes a multipronged metabolic hit to C. auris: it restricts the micronutrient iron to potentiate nutritional immunity imposed by immune cells, and it further causes metabolic dysfunction that compromises the utilization of macronutrients, thereby curbing the metabolic plasticity needed for growth in host environments. Our study offers a new avenue for therapeutic development against drug-resistant C. auris, shows how complex metabolic dysfunction can be caused by a single compound triggering antifungal inhibition, and provides insights into the metabolic needs of C. auris in immune cell environments.IMPORTANCE Over the last decade, Candida auris has emerged as a human pathogen around the world causing life-threatening infections with wide-spread antifungal drug resistance, including pandrug resistance in some cases. In this study, we addressed the mechanism of action of the antiparasitic drug pyrvinium pamoate against C. auris and show how metabolism could be inhibited to curb C. auris proliferation. We show that pyrvinium pamoate triggers sweeping metabolic and mitochondrial changes and disrupts iron homeostasis. PP-induced metabolic dysfunction compromises the utilization of both micro- and macronutrients by C. auris and reduces its growth in vitro and in immune phagocytes. Our findings provide insights into the metabolic requirements for C. auris growth and define the mechanisms of action of pyrvinium pamoate against C. auris, demonstrating how this compound works by inhibiting the metabolic flexibility of the pathogen. As such, our study characterizes credible avenues for new antifungal approaches against C. auris.

Iron Dysregulation in Mitochondrial Dysfunction and Alzheimer's Disease.

Alzheimer’s disease (AD) is a devastating progressive neurodegenerative disease characterized by neuronal dysfunction, and decreased memory and cognitive function. Iron is critical for neuronal activity, neurotransmitter biosynthesis, and energy homeostasis. Iron accumulation occurs in AD and results in neuronal dysfunction through activation of multifactorial mechanisms. Mitochondria generate energy and iron is a key co-factor required for: (1) ATP production by the electron transport chain, (2) heme protein biosynthesis and (3) iron-sulfur cluster formation. Disruptions in iron homeostasis result in mitochondrial dysfunction and energetic failure. Ferroptosis, a non-apoptotic iron-dependent form of cell death mediated by uncontrolled accumulation of reactive oxygen species and lipid peroxidation, is associated with AD and other neurodegenerative diseases. AD pathogenesis is complex with multiple diverse interacting players including Aβ-plaque formation, phosphorylated tau, and redox stress. Unfortunately, clinical trials in AD based on targeting these canonical hallmarks have been largely unsuccessful. Here, we review evidence linking iron dysregulation to AD and the potential for targeting ferroptosis as a therapeutic intervention for AD.

The role of disrupted iron homeostasis in the development and progression of arthropathy.

Arthropathy or joint disease leads to significant pain and disability irrespective of etiology. Clinical and experimental evidence point to the presence of considerable links between arthropathy and iron overload. Previous work has suggested that iron accumulation in the joints isoften associated with increased oxidative stress, disrupted matrix metabolism, and cartilage degeneration. However, key issues regarding the role of iron overload in the pathogenesis of arthropathy remain ambiguous. For example, significant gaps in our knowledge of the primary cellular targets of iron overload-induced damage and the exact molecular mechanism through which disrupted iron homeostasis leads to joint damage still exist. The exact signaling pathway that links iron metabolism and cellular damage in arthropathy also remains largely unmapped. In this review, we focus on the relationship between iron overload and arthropathy with special emphasis on the adversarial relationship between iron that accumulates in the joints over time and cartilage homeostasis. A better understanding of the mechanisms and pathways underlying iron-induced cartilage degeneration may help in defining new prognostic markers and therapeutic targets in arthropathy.

Comparative functional genomics identifies an iron-limited bottleneck in a Saccharomyces cerevisiae strain with a cytosolic-localized isobutanol pathway

Metabolic engineering strategies have been successfully implemented to improve the production of isobutanol, a next-generation biofuel, in Saccharomyces cerevisiae. Here, we explore how two of these strategies, pathway re-localization and redox cofactor-balancing, affect the performance and physiology of isobutanol producing strains. We equipped yeast with isobutanol cassettes which had either a mitochondrial or cytosolic localized isobutanol pathway and used either a redox-imbalanced (NADPH-dependent) or redox-balanced (NADH-dependent) ketol-acid reductoisomerase enzyme. We then conducted transcriptomic, proteomic and metabolomic analyses to elucidate molecular differences between the engineered strains. Pathway localization had a large effect on isobutanol production with the strain expressing the mitochondrial-localized enzymes producing 3.8-fold more isobutanol than strains expressing the cytosolic enzymes. Cofactor-balancing did not improve isobutanol titers and instead the strain with the redox-imbalanced pathway produced 1.5-fold more isobutanol than the balanced version, albeit at low overall pathway flux. Functional genomic analyses suggested that the poor performances of the cytosolic pathway strains were in part due to a shortage in cytosolic Fe–S clusters, which are required cofactors for the dihydroxyacid dehydratase enzyme. We then demonstrated that this cofactor limitation may be partially recovered by disrupting iron homeostasis with a fra2 mutation, thereby increasing cellular iron levels. The resulting isobutanol titer of the fra2 null strain harboring a cytosolic-localized isobutanol pathway outperformed the strain with the mitochondrial-localized pathway by 1.3-fold, demonstrating that both localizations can support flux to isobutanol.

Iron Promotes Cardiac Doxorubicin Retention and Toxicity Through Downregulation of the Mitochondrial Exporter ABCB8.

In several cancers, the efflux and resistance against doxorubicin (DOX), an effective anticancer drug, are associated with cellular iron deficiency and overexpression of the mitochondrial exporter ABCB8. Conversely, decreased ABCB8 expression and disrupted iron homeostasis in the heart have been implicated in DOX-associated cardiotoxicity. While studies have demonstrated that altered iron status can modulate the susceptibility to DOX cardiotoxicity, the exact molecular mechanisms have not been clearly understood. Here, we hypothesized that iron stores influence cardiac ABCB8 expression and consequently cardiac retention and toxicity of DOX. First, we found that ABCB8 deficiency in cardiomyocytes decreased DOX efflux, increased DOX-induced toxicity, and decreased cell viability. Conversely, intracellular DOX retention and toxicity were ameliorated by ABCB8 overexpression. To determine if altered cardiac iron status modifies ABCB8 expression, we treated cardiomyocytes with high iron or iron chelators. Western blot and qPCR analyses revealed that ABCB8 levels were decreased in iron overload and increased in iron deficiency. Subsequently, DOX retention and toxicity were increased in cardiomyocytes with iron overload, whereas iron deficiency ameliorated these effects. Next, we validated our results using a mouse model of hereditary hemochromatosis (HH), a genetic iron overload disorder. HH mice exhibited decreased ABCB8 expression and increased DOX retention and toxicity. These changes were abolished by the treatment of HH mice with a low-iron diet. Finally, cardiac-specific overexpression of ABCB8 in HH mice prevented cardiac DOX accumulation and abrogated DOX-induced cardiotoxicity without altering iron overload in the heart. Together, our results demonstrate that ABCB8 mediates DOX efflux and that iron regulates DOX retention and toxicity by altering cardiac ABCB8 expression. Our study identifies a novel role of iron in DOX-induced cardiotoxicity and suggests potential therapeutic intervention for DOX and anthracycline-based cancer pharmacology.

The biology of mammalian multi-copper ferroxidases.

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.

6-Hydroxydopamine Induces Abnormal Iron Sequestration in BV2 Microglia by Activating Iron Regulatory Protein 1 and Inhibiting Hepcidin Release.

Disrupted iron homeostasis in the substantia nigra pars compacta (SNpc) is an important pathological mechanism in Parkinson’s disease (PD). It is unclear what role microglia play in iron metabolism and selective iron deposition in the SNpc of PD brain. In this study, we observed that 6-hydroxydopamine (6-OHDA) induced the expression of divalent metal transporter-1 (DMT1) and iron influx in BV2 microglia cells, which might be associated with the upregulation of iron regulatory protein 1 (IRP1) expression. Moreover, we found that 6-OHDA had no significant effect on the expression of ferroportin 1 (FPN1) and iron efflux in BV2 microglial cells, which might be the combined action of IRP1 upregulation and reduced hepcidin levels. Furthermore, 6-OHDA treatment activated BV2 microglia and enhanced the release of pro-inflammatory cytokines. Interestingly, iron overloading suppressed IRP1 expression, thus downregulating DMT1 and upregulating FPN1 levels in these microglial cells. On the contrary, iron deficiency activated IRP1, leading to increased expression of DMT1 and decreased expression of FPN1—which indicates that activated IRP1 induces iron overloading in 6-OHDA-treated microglia, but not iron overloading modulates the expression of IRP1. Taken together, our data suggest that 6-OHDA can regulate the expression of DMT1 and FPN1 by activating IRP1 and inhibiting hepcidin release, thus leading to abnormal iron sequestration in microglia. In addition, 6-OHDA can activate microglia, which leads to increased release of pro-inflammatory factors that can further induce genome damage in dopaminergic neurons.

Drosophila ZIP13 over-expression or transferrin1 RNAi influences the muscle degeneration of Pink1 RNAi by elevating iron levels in mitochondria.

Disruption of iron homeostasis in the brain of Parkinson's disease (PD) patients has been reported for many years, but the underlying mechanisms remain unclear. To investigate iron metabolism genes related to PTEN-induced kinase 1 (Pink1) and parkin (E3 ubiquitin ligase), two PD-associated proteins that function to coordinate mitochondrial turnover via induction of selective mitophagy, we conducted a genetic screen in Drosophila and found that altered expression of genes involved in iron metabolism, such as Drosophila ZIP13 (dZIP13) or transferrin1 (Tsf1), significantly influences the disease progression related to Pink1 but not parkin. Several phenotypes of Pink1 mutant and Pink1 RNAi but not parkin mutant were significantly rescued by over-expression (OE) of dZIP13 (dZIP13 OE) or silencing of Tsf1 (Tsf1 RNAi) in the flight muscles. The rescue effects of dZIP13 OE or Tsf1 RNAi were not exerted through mitochondrial disruption or mitophagy; instead, the iron levels in mitochondira were significantly increased, resulting in enhanced activities of enzymes participating in respiration and increased ATP synthesis. Consistently, the rescue effects of dZIP13 OE or Tsf1 RNAi on Pink1 RNAi can be inhibited by decreasing the iron levels in mitochondria through mitoferrin (dmfrn) RNAi. This study suggests that dZIP13, Tsf1, and dmfrn might act independently of parkin in a parallel pathway downstream of Pink1 by modulating respiration and indicates that manipulation of iron levels in mitochondria may provide a novel therapeutic strategy for PD associated with Pink1.

Cigarette Smoke Particle-Induced Lung Injury and Iron Homeostasis.

It is proposed that the mechanistic basis for non-neoplastic lung injury with cigarette smoking is a disruption of iron homeostasis in cells after exposure to cigarette smoke particle (CSP). Following the complexation and sequestration of intracellular iron by CSP, the host response (eg, inflammation, mucus production, and fibrosis) attempts to reverse a functional metal deficiency. Clinical manifestations of this response can present as respiratory bronchiolitis, desquamative interstitial pneumonitis, pulmonary Langerhans’ cell histiocytosis, asthma, pulmonary hypertension, chronic bronchitis, and pulmonary fibrosis. If the response is unsuccessful, the functional deficiency of iron progresses to irreversible cell death evident in emphysema and bronchiectasis. The subsequent clinical and pathological presentation is a continuum of lung injuries, which overlap and coexist with one another. Designating these non-neoplastic lung injuries after smoking as distinct disease processes fails to recognize shared relationships to each other and ultimately to CSP, as well as the common mechanistic pathway (ie, disruption of iron homeostasis).

Iron Homeostasis in Pseudomonas aeruginosa: Targeting Iron Acquisition and Storage as an Antimicrobial Strategy.

Pseudomonas aeruginosa causes a wide array of life-threatening acute and chronic infections in humans. This opportunistic pathogen is metabolically highly versatile and harbors multiple virulence factors that allow infection of essentially any organ of the human body. The high capacity of this bacterium to acquire iron facilitates its versatility and is considered one of the P. aeruginosa virulence hallmarks. Iron functions as a redox cofactor of enzymes required for vital biological processes and is thus essential for all living organisms. However, in aerobic environments, iron is mainly present in its ferric form, which is insoluble and poorly bioavailable. This problem increases in the human body because, as a reaction to the infection, the host induces a "nutritional immunity" response aiming to reduce the amount of iron available for invading microorganisms. P. aeruginosa contains several mechanisms for iron acquisition including (1) production of siderophores pyoverdine and pyochelin; (2) use of xenosiderophores produced by other microorganisms; (3) direct transport of ferrous ions; and (4) utilization of host iron carriers (e.g., heme). However, although essential, iron results toxic when present in excess because it facilitates the production of reactive oxygen species (ROS) that damage bacterial cells. P. aeruginosa contains ferritins and efflux systems for iron withdrawal to avoid excess of this metal. Production of iron acquisition and removal systems is highly regulated to ensure sufficient iron for metabolic needs while preventing its toxicity. This chapter covers the different mechanisms used by P. aeruginosa to maintain iron homeostasis, which is vital for this pathogen to grow and proliferate in the host. We also highlight current strategies to block P. aeruginosa infections by disrupting iron homeostasis.

PPAR-α Agonist GW7647 Protects Against Oxidative Stress and Iron Deposit via GPx4 in a Transgenic Mouse Model of Alzheimer's Diseases.

Alzheimer's disease (AD) is a neurodegenerative disease caused by lipid peroxidation and iron hemostasis of the brain. PPAR-α is regarded as the most encouraging therapeutic approach of several neurodegenerative and metabolic disorders, due to its potent regulatory effects. In this study, we examined the ameliorative effect and the mechanisms of a PPAR-α agonist, GW7647, on the established AD models using APP/PS1 mice and APPsw/SH-SY5Y cells. Through Aβ quantification and behavioral test, we found that GW7647 reduced Aβ burden and improved cognitive defect in APP/PS1 mice. Liquid chromatography-mass spectrometry analysis indicated that GW7647 could enter the brain after oral administration. Neuronal cell death and iron deposit were inhibited, accompanied by decreased lipid peroxidation and inflammation. In an in vitro study of APPsw cells, we found that PPAR-α directly bound with GPx4 intron3 to promote GPx4 transcription and reduced the iron transport capability. Our data suggested that activation of PPAR-α by GW7647 improved the disruption of iron homeostasis in the brain of APP/PS1 mice and alleviated neuronal inflammation and lipid peroxidation, which was possibly related to the upregulated transcription of GPx4 mediated by the interaction of GPx4 noncoding region and the PPAR-α.

CBIO-06. CELL INTRINSIC HFE DRIVES SEX-SPECIFIC GLIOBLASTOMA GROWTH

Abstract Iron is an essential element required for a number of cellular processes and can contribute to malignant transformation and tumor expansion. In glioblastoma (GBM), tumor cells have been shown to modulate expression of iron-associated proteins to enhance iron uptake from the surrounding microenvironment, driving proliferation and tumor growth. The homeostatic iron regulatory (HFE) gene encodes a transmembrane glycoprotein that aids in iron homeostasis by modulating iron uptake and release. HFE is upregulated in GBM tumors compared to non-tumor brain and expression of HFE increases with tumor grade. Furthermore, HFE mRNA expression is associated with significantly reduced survival specifically in female patients with GBM. However, it is unclear how HFE impacts sex-specific GBM growth. To interrogate the underlying mechanism of HFE-mediated sex differences, we employed genetic loss and gain of function approaches using syngeneic mouse glioma models. We observed significant alterations in the expression of several iron-associated genes with Hfe knockdown or overexpression, suggesting global disruption of iron homeostasis. We found that knockdown of Hfe decreased cell number and increased apoptosis in vitro and led to a significant impairment of tumor growth in vivo, with a more pronounced effect seen in female mice. Conversely, overexpression of Hfe increased cell number and significantly decreased survival only in female animals. These findings support the hypothesis that Hfe is a critical regulator of cellular iron status and contributes to tumor aggression in a sex-dependent manner. These data also suggest an unexplored link between cell intrinsic iron signaling and sex-specific microenvironmental and immune responses, which is the focus of ongoing studies.

Ferritinophagy is Involved in Experimental Subarachnoid Hemorrhage-Induced Neuronal Ferroptosis.

Ferroptosis is a novel form of regulated cell death involved in the pathophysiological process of experimental subarachnoid hemorrhage (SAH), but how neuronal ferroptosis occurs remains unknown. In this study, we report that SAH-induced ferroptosis is macroautophagy/autophagy dependent because the inhibition of autophagy by knocking out autophagy-related gene 5 (ATG5) apparently mitigated SAH-induced ferroptosis. We created an experimental SAH model in Sprague-Dawley rats to determine the possible mechanism. We found that SAH can trigger neuronal ferroptosis, as evidenced by the disruption of ironhomeostasis, elevation of intracellular lipid peroxidation (LPO) and decreased expression of ferroptosis-protective proteins. Then, we inhibited autophagy byATG5gene knockout, showing thatautophagy inhibition can reduce the intracellular iron level and LPO, improve the expression of ferroptosis-protective proteins, and subsequently alleviate SAH-induced cell death. Additionally, autophagy inhibition also attenuated SAH prognostic indicators, such as brain edema, blood-brain barrier permeability, and neurological deficits. These findings not only present an opinion that SAH triggers neuronal ferroptosis via activation of ferritinophagy but also indicate that regulating ferritinophagy and maintaining ironhomeostasis could provide clues for the prevention of early brain injury.

GSK-3\u03b2 manipulates ferroptosis sensitivity by dominating iron homeostasis

Ferroptosis is a newly characterized form of non-apoptotic-programmed cell death, which is driven by the lethal accumulation of iron-catalyzed lipid peroxides. Uncontrolled ferroptosis is implicated in the pathogenesis of a group of human diseases, while targeted induction of ferroptosis provides a potent therapeutic design for cancers. During the past decade, the fundamental regulatory circuits of ferroptosis have been identified. In this study, we show that the multifaceted Ser/Thr protein kinase GSK-3β acts as a positive modulator of the ferroptosis program. Pharmacological inhibition of GSK-3β by selective inhibitor LY2090314 or genetic KD of GSK-3β by shRNA potently promotes ferroptotic resistance. GSK-3β KD antagonizes the expression of iron metabolic components including DMT1, FTH1, and FTL, leading to the disruption of iron homeostasis and decline in intracellular labile free iron level. Taken together, our findings elaborate an indispensable role of GSK-3β in determining ferroptotic sensitivity by dominating cellular iron metabolism, which provides further insight into GSK-3β as a target for cancer chemotherapy.

Association between obesity and iron deficiency (Review).

Obesity is a risk factor for several comorbidities and complications, including iron deficiency anemia. Iron deficiency anemia is a serious global public health problem, with a worldwide prevalence. The high prevalence of obesity in combination with iron deficiency incidence observed in different age and sex categories suggests an association between obesity and iron status. Obesity may disrupt iron homeostasis, resulting in iron deficiency anemia. The association between obesity and iron deficiency may be due to increased hepcidin levels mediated by chronic inflammation. Hepcidin is a small peptide hormone that functions as a negative regulator of intestinal iron absorption. Significant body weight loss in overweight and obese individuals decreases chronic inflammation and serum hepcidin levels, resulting in improved iron status due to increased iron absorption. However, further randomized controlled trials are required to confirm this effect.

Engineering Amyloid Aggregation as a New Way to Eliminate Cancer Stem Cells by the Disruption of Iron Homeostasis.

Cancer stem cells (CSCs) play crucial roles in tumor initiation. Amyloid β (Aβ), which is associated with Alzheimer's disease (AD), has been identified to induce cytotoxicity in tumor cells besides brain cells. Herein, we find that oligomeric Aβ1-42 and Aβ1-40 (OAβ1-42 and OAβ1-40) can repress the viability of breast CSCs. Intriguingly, OAβ1-42 and OAβ1-40 preferentially induce the growth arrest of breast CSCs by contrast with the bulk cancer cells. Further studies indicate that OAβ1-42 and OAβ1-40 disturb iron homeostasis, which results in iron accumulation in lysosomes. The iron in lysosomes then induces ROS production by Fenton reaction, leading to breast CSC death. In vivo experiments show that the tumorigenesis of breast CSCs pretreated with OAβ1-42 is inhibited. These results reveal that OAβ1-42 and OAβ1-40 are multifaceted players with the ability to eliminate CSCs. Our work may provide a new clue to better understand the biological functions of amyloid oligomers.

Diacetyl exposure disrupts iron homeostasis in animals and cells

Objective Several mechanisms have been proposed for the biological effect of diacetyl. We tested the postulate that animal and cell exposures to diacetyl are associated with a disruption in iron homeostasis. Materials and methods Male, Sprague–Dawley rats were intratracheally-instilled with either distilled water or diacetyl. Seven days after treatment, animals were euthanized and the lungs removed, fixed, and embedded. Sections were cut and stained for iron, collagen, and ferritin. Human epithelial (BEAS-2B) and monocytic (THP-1) cells were exposed in vitro to ferric ammonium citrate (FAC), diacetyl, and both FAC and diacetyl. Cell non-heme iron concentrations and ferritin levels were quantified using inductively coupled plasma optical emission spectroscopy and an immunoassay respectively. Results After exposure of animals to diacetyl, there were airway polypoid lesions which stained positively for both iron and the intracellular storage protein ferritin. Trichrome stain showed a deposition of collagen immediately adjacent to accumulated metal following diacetyl exposure. In in vitro cell exposures, FAC increased non-heme iron concentration but co-incubations of FAC and diacetyl elevated levels to significantly greater values. Levels of ferritin were increased with exposures of BEAS-2B and THP-1 cells to FAC but were similarly greater after co-exposure with FAC and diacetyl. Conclusions Results of animal and cell studies support a disruption of iron homeostasis by diacetyl. It is proposed that, following internalization, diacetyl complexes intracellular sources of iron. The cell recognizes a loss of its requisite iron to diacetyl and imports greater concentrations of the metal.