Intestinal iron absorption is appropriately modulated to match physiological demand for iron in wild-type and iron-loaded Hamp (hepcidin) knockout rats during acute colitis

Mucosal damage, barrier breach, inflammation, and iron-deficiency anemia (IDA) typify ulcerative colitis (UC) in humans. The anemia in UC appears to mainly relate to systemic inflammation. The pathogenesis of this ‘anemia of inflammation’ (AI) involves cytokine-mediated transactivation of hepatic Hamp (encoding the iron-regulatory hormone, hepcidin). In AI, high hepcidin represses iron absorption (and iron release from stores), thus lowering serum iron, and restricting iron for erythropoiesis (causing anemia). In less-severe disease states, inflammation may be limited to the intestine, but whether this perturbs iron homeostasis is uncertain. We hypothesized that localized gut inflammation will increase overall iron demand (to support the immune response and tissue repair), and that hepatic Hamp expression will decrease in response, thus derepressing (i.e., enhancing) iron absorption. Accordingly, we developed a rat model of mild, acute colitis, and studied iron absorption and homeostasis. Rats exposed (orally) to DSS (4%) for 7 days had intestinal (but not systemic) inflammation, and biomarker analyses demonstrated that iron utilization was elevated. Iron absorption was enhanced (by 2-3-fold) in DSS-treated, WT rats of both sexes, but unexpectedly, hepatic Hamp expression was not suppressed. Therefore, to gain a better understanding of regulation of iron absorption during acute colitis, Hamp KO rats were used for further experimentation. The severity of DSS-colitis was similar in Hamp KOs as in WT controls. In the KOs, increased iron requirements associated with the physiological response to colitis were satisfied by mobilizing hepatic storage iron, rather than by increasing absorption of enteral iron (as occurred in WT rats). In conclusion then, in both sexes and genotypes of rats, iron absorption was appropriately modulated to match physiological demand for dietary iron during acute intestinal inflammation, but regulatory mechanisms may not involve hepcidin.

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Mechanistic and regulatory aspects of intestinal iron absorption

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00348.2013 ◽

2014 ◽

Vol 307 (4) ◽

pp. G397-G409 ◽

Cited By ~ 119

Author(s):

Sukru Gulec ◽

Gregory J. Anderson ◽

James F. Collins

Keyword(s):

Iron Homeostasis ◽

Iron Absorption ◽

Hereditary Hemochromatosis ◽

Regulatory Protein ◽

Whole Body ◽

Deficiency Anemia ◽

Inherited Disorders ◽

Intestinal Iron Absorption ◽

Body Iron ◽

Proximal Small Bowel

Iron is an essential trace mineral that plays a number of important physiological roles in humans, including oxygen transport, energy metabolism, and neurotransmitter synthesis. Iron absorption by the proximal small bowel is a critical checkpoint in the maintenance of whole-body iron levels since, unlike most other essential nutrients, no regulated excretory systems exist for iron in humans. Maintaining proper iron levels is critical to avoid the adverse physiological consequences of either low or high tissue iron concentrations, as commonly occurs in iron-deficiency anemia and hereditary hemochromatosis, respectively. Exquisite regulatory mechanisms have thus evolved to modulate how much iron is acquired from the diet. Systemic sensing of iron levels is accomplished by a network of molecules that regulate transcription of the HAMP gene in hepatocytes, thus modulating levels of the serum-borne, iron-regulatory hormone hepcidin. Hepcidin decreases intestinal iron absorption by binding to the iron exporter ferroportin 1 on the basolateral surface of duodenal enterocytes, causing its internalization and degradation. Mucosal regulation of iron transport also occurs during low-iron states, via transcriptional (by hypoxia-inducible factor 2α) and posttranscriptional (by the iron-sensing iron-regulatory protein/iron-responsive element system) mechanisms. Recent studies demonstrated that these regulatory loops function in tandem to control expression or activity of key modulators of iron homeostasis. In health, body iron levels are maintained at appropriate levels; however, in several inherited disorders and in other pathophysiological states, iron sensing is perturbed and intestinal iron absorption is dysregulated. The iron-related phenotypes of these diseases exemplify the necessity of precisely regulating iron absorption to meet body demands.

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Skeletal muscle hemojuvelin is dispensable for systemic iron homeostasis

Blood ◽

10.1182/blood-2010-12-327957 ◽

2011 ◽

Vol 117 (23) ◽

pp. 6319-6325 ◽

Cited By ~ 39

Author(s):

Wenjie Chen ◽

Franklin W. Huang ◽

Tomasa Barrientos de Renshaw ◽

Nancy C. Andrews

Keyword(s):

Skeletal Muscle ◽

Iron Homeostasis ◽

Iron Absorption ◽

Conditional Knockout ◽

Dietary Iron ◽

Iron Release ◽

Hepcidin Expression ◽

Morphogenetic Protein ◽

Smad Signaling Pathway ◽

Very High

Abstract Hepcidin, a hormone produced mainly by the liver, has been shown to inhibit both intestinal iron absorption and iron release from macrophages. Hemojuvelin, a glycophosphatidyl inositol–linked membrane protein, acts as a bone morphogenetic protein coreceptor to activate hepcidin expression through a SMAD signaling pathway in hepatocytes. In the present study, we show in mice that loss of hemojuvelin specifically in the liver leads to decreased liver hepcidin production and increased tissue and serum iron levels. Although it does not have any known function outside of the liver, hemojuvelin is expressed at very high levels in cardiac and skeletal muscle. To explore possible roles for hemojuvelin in skeletal muscle, we analyzed conditional knockout mice that lack muscle hemojuvelin. The mutant animals had no apparent phenotypic abnormalities. We found that systemic iron homeostasis and liver hepcidin expression were not affected by loss of hemojuvelin in skeletal muscle regardless of dietary iron content. We conclude that, in spite of its expression pattern, hemojuvelin is primarily important in the liver.

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Modulation of the HIF2-NCOA4 axis in enterocytes attenuates iron loading in a mouse model of hemochromatosis

Blood ◽

10.1182/blood.2021013452 ◽

2022 ◽

Author(s):

Nupur K Das ◽

Chesta Jain ◽

Amanda D. Sankar ◽

Andrew J Schwartz ◽

Naiara Santana-Codina ◽

...

Keyword(s):

Iron Deficiency ◽

Mouse Model ◽

Iron Overload ◽

Iron Homeostasis ◽

Iron Absorption ◽

Hypoxia Inducible Factor ◽

Whole Body ◽

Deficiency Anemia ◽

Null Mouse ◽

Intestinal Iron Absorption

Intestinal iron absorption is activated during increased systemic iron demand. The best-studied example is iron-deficiency anemia, which increases intestinal iron absorption. Interestingly, the intestinal response to anemia is very similar to that of iron overload disorders, as both the conditions activate a transcriptional program that leads to a hyperabsorption of iron via the transcription factor hypoxia-inducible factor (HIF)2a. However, pathways to selectively target intestinal-mediated iron overload remain unknown. Nuclear receptor co-activator 4 (NCOA4) is a critical cargo receptor for autophagic breakdown of ferritin (FTN) and subsequent release of iron, in a process termed ferritinophagy. Our work demonstrates that NCOA4-mediated intestinal ferritinophagy is integrated to systemic iron demand via HIF2a. To demonstrate the importance of intestinal HIF2a/ferritinophagy axis in systemic iron homeostasis, whole body and intestine-specific NCOA4-null mouse lines were generated and assessed. These analyses revealed that the intestinal and systemic response to iron deficiency was not altered following disruption of intestinal NCOA4. However, in a mouse model of hemochromatosis, ablation of intestinal NCOA4 was protective against iron overload. Therefore, NCOA4 can be selectively targeted for the management of iron overload disorders without disrupting the physiological processes involved in the response to systemic iron deficiency.

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Influence of Infection/Inflammation, Thalassemia and Nutritional Status on Iron Absorption

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.77.3.217 ◽

2007 ◽

Vol 77 (3) ◽

pp. 217-223 ◽

Cited By ~ 14

Author(s):

Lynch

Keyword(s):

Iron Homeostasis ◽

Iron Absorption ◽

Inflammatory Diseases ◽

Acid Output ◽

Peptide Hormone ◽

Thalassemia Major ◽

Human Beings ◽

Iron Release ◽

Iron Stores ◽

Gluten Enteropathy

Iron balance in human beings is maintained by the control of absorption. Recent observations have demonstrated that a peptide hormone, hepcidin, is the principal regulator of iron homeostasis. It is produced in the liver in response to increasing iron stores. It is also induced by interleukin-6 (IL-6) in infectious and inflammatory diseases. Hepcidin restricts both iron absorption and iron release from stores. Disorders that affect the duodenum or stomach directly, particularly gluten enteropathy and H. pylori infections, also impair iron absorption by damaging enterocytes or reducing gastric acid output. Hepcidin secretion is suppressed by accelerated erythropoiesis even when iron stores are increased. This appears to account for the contribution that excessive absorption makes to the iron overload seen in patients with iron-loading anemias such as thalassemia major. There is some evidence suggesting that two nutritional deficiency disorders (deficiencies of vitamin A and riboflavin) lead to impaired iron absorption or utilization, but further research is needed to reconcile conflicting experimental observations.

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Systemic iron homeostasis in female athletes: hepcidin, exercise and sex influence

Archivos de Medicina del Deporte ◽

10.18176/archmeddeporte.0009 ◽

2020 ◽

Vol 37 (5) ◽

pp. 348-353

Author(s):

L Barba-Moreno ◽

VM Alfaro-Magallanes ◽

FJ Calderón ◽

AB Peinado

Keyword(s):

Iron Deficiency ◽

Iron Homeostasis ◽

Female Athletes ◽

Iron Absorption ◽

The Body ◽

Deficiency Anemia ◽

Hormonal Changes ◽

Sexual Hormones ◽

Susceptible Population ◽

And Performance

Iron is necessary for adequate deliver oxygen to the tissues since it is an essential component of the haemoglobin. However, iron deficiency remains a common problem among athletes, particularly for women experiencing the menstrual bleeding every month. The iron losses through menstrual blood loss during the early follicular phase (or menses) and an inadequate dietary intake of iron are two important factors contributing to this disease. Furthermore, the large hormonal changes that women experience along the menstrual cycle, especially in oestrogen and progesterone may influence on the optimization of iron absorption. Iron absorption is mainly mediated by hepcidin hormone, which seems to be affected by several stimulus and factors such as oestrogen and progesterone concentrations. Moreover, the regular practice of exercise is another important modulator of this hormone. Therefore, premenopausal active females are the most susceptible population to develop an iron deficiency or iron deficiency anemia, affecting their health and performance due to the less iron availability within the body and consequently a reduction of haemoglobin which compromise the oxygen transport. To date, most studies have not explored the acute post-exercise hepcidin response taking endogenous and exogenous sexual hormones influence into account. This narrative review will focus on how iron homeostasis is modulated by different factors mainly influenced by exercise and female sexual hormones.

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Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice

Blood ◽

10.1182/blood-2010-10-315507 ◽

2011 ◽

Vol 117 (17) ◽

pp. 4590-4599 ◽

Cited By ~ 56

Author(s):

Karin E. Finberg ◽

Rebecca L. Whittlesey ◽

Nancy C. Andrews

Keyword(s):

Iron Deficiency ◽

Iron Homeostasis ◽

Target Genes ◽

Genetic Modifier ◽

Hereditary Hemochromatosis ◽

Deficiency Anemia ◽

Iron Release ◽

Independent Manner ◽

Smad Signaling ◽

Hepatic Expression

Abstract The hereditary hemochromatosis protein HFE promotes the expression of hepcidin, a circulating hormone produced by the liver that inhibits dietary iron absorption and macrophage iron release. HFE mutations are associated with impaired hepatic bone morphogenetic protein (BMP)/SMAD signaling for hepcidin production. TMPRSS6, a transmembrane serine protease mutated in iron-refractory iron deficiency anemia, inhibits hepcidin expression by dampening BMP/SMAD signaling. In the present study, we used genetic approaches in mice to examine the relationship between Hfe and Tmprss6 in the regulation of systemic iron homeostasis. Heterozygous loss of Tmprss6 in Hfe−/− mice reduced systemic iron overload, whereas homozygous loss caused systemic iron deficiency and elevated hepatic expression of hepcidin and other Bmp/Smad target genes. In contrast, neither genetic loss of Hfe nor hepatic Hfe overexpression modulated the hepcidin elevation and systemic iron deficiency of Tmprss6−/− mice. These results indicate that genetic loss of Tmprss6 increases Bmp/Smad signaling in an Hfe-independent manner that can restore Bmp/Smad signaling in Hfe−/− mice. Furthermore, these results suggest that natural genetic variation in the human ortholog TMPRSS6 might modify the clinical penetrance of HFE-associated hereditary hemochromatosis, raising the possibility that pharmacologic inhibition of TMPRSS6 could attenuate iron loading in this disorder.

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Study on Sucrosomial® Iron Endocytosis-Mediated Uptake and Enterocytes Release

Blood ◽

10.1182/blood-2018-99-114523 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4892-4892

Author(s):

Elisa Brilli ◽

Asperti Michela ◽

Magdalena Gryzik ◽

Alessandro Lucchesi ◽

Giovanni Martinelli ◽

...

Keyword(s):

Hepg2 Cells ◽

Iron Uptake ◽

Iron Homeostasis ◽

Iron Absorption ◽

Phospholipid Bilayer ◽

Ammonium Citrate ◽

Ferric Ammonium Citrate ◽

Iron Release ◽

Iron Storage

Abstract Introduction: iron homeostasis is maintained by regulating the iron levels in plasma which is maintained by four coordinated processes: duodenal iron absorption, macrophage iron recycling, hepatic iron storage and erythropoiesis. Iron in the Fe2+ form is transported across the apical duodenal membrane by DMT1 and subsequently transferred to the blood via the iron exporter, Ferroportin the only know cell membrane iron exporter. Due to the presence of two check points at cellular levels, iron absorption and release are mainly regulated, because of this iron containing oral formulations are poorly absorbed and bioavailable. To overcome cellular barriers and increasing the bioavailability of supplemented iron forms, there is a need for new carriers that work protecting the iron as well as enhancing its intestinal absorption and release into the blood stream. Moreover thus reducing dosage and side effects. Sucrosomial® Iron (SI) represents an innovative oral iron-containing carrier in which ferric pyrophosphate is protected by a phospholipid bilayer membrane plus a sucrester matrix. To date, in vitro studies have shown that SI is mostly absorbed as vesicle-like structure, bypassing the conventional iron absorption pathway. Due to its behaviour at the gastrointestinal tract, SI is well tolerated and highly bioavailable compared to conventional iron salts. To deeply understand involvement of endocytosis in SI absorption and release, in vitro experiments using endocytosis and ferroportin inhibitors were carried out Aim: to study Sucrosomial® Iron uptake and release in different in vitro systems. Materials and Methods: CACO-2 and THP1 cells were used to investigate the role of FPN in Sucorsomial Iron release from cells. For release study, CACO-2 cells were exposed for 18h to quercetin (150mmol/L) in order to downregulate FPN expression. CACO-2 quercetin pre-treated cells were co-cultured with TPH1 cells, and SI or FAC were added. However, prior to measure cell Ferritin content, the incubation medium was discarded and cells were washed to remove quercetin. Iron uptake-release analysis was performed using co-culture transwell system between CACO-2 cells and TPH1. To investigate the cellular fate of cellular iron in quercetin treated CACO-2 and TPH1 cells we measured cell ferritin content. To inhibit endocytosis absorption pathway, CACO-2, THP1 and HepG2 cells were pre-treated with PitStop2 and Dyngo 4a inhibitors and then treated with SI, or Ferrous Sulfate (FS) or ferric ammonium citrate (FAC). Cellular Ferritin content was measured. Results: in order to understand the effect of quercetin on iron storage, we used CACO2 and TPH1 cells pre-treated with quercetin and then treated with SI, FAC or nothing (control). Quercetin-SI treated CACO-2 cells showed no differences in Ferritin expression compared to control cells (3,94 ngFTL/mg proteins Vs 4,56 ngFTL/mg proteins) while in quercetin-FAC treated cells ferritin expression was decreased compare to control cells (16,3 ngFTL/mg proteins Vs 27,55 ngFTL/mg proteins). In a similar manner, quercetin-SI treated TPH1 cells didn't show increase in Ferritin expression compared to control cells (20 ngFTL/mg proteins Vs 15,15 ngFTL/mg proteins), only in quercetin-FAC treated cells we observed a Ferritin expression increase compared to control untreated cells (16 ngFTL/mg proteins Vs 24 ngFTL/mg proteins). Results from experiments using endocytosis inhibitors showed that SI absorption in CACO-2 cells is inhibited using Dyngo4a (from 4ngFTL/mg proteins to 0,36 ngFTL/ mg proteisn) while PitStop3 seems to reduce SI absorption in THP1 (from 396 ngFL/mg protein to 199,91 ngFTL/mg proteins) and HepG2 cells (from 26,86 ngFL/mg proteins to 3,93 ngFTL/mg proteins), since ferritin expression significantly decrease only in SI treated cells. Conclusions: endocytosis pathway seems to be involved in SI cellular uptake but this process is regulated in different manner probably due to different cell types. Release experiments showed that cells treated with quercetin could reduce for a negative feedback DMT1 expression as well, affecting iron uptake from cells treated with FAC but not with SI and consequently, if SI is able to bypass commonly iron uptake mechanism, FPN inhibition did not show iron release perturbation from cells treated with SI. Disclosures Brilli: Pharmanutra s.p.a.: Consultancy. Martinelli:Janssen: Consultancy; Pfizer: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Roche: Consultancy; Abbvie: Consultancy; Novartis: Speakers Bureau; Amgen: Consultancy; Ariad/Incyte: Consultancy; Jazz Pharmaceuticals: Consultancy. Tarantino:Pharmanutra s.p.a.: Employment.

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Hepcidin regulates ferroportin expression and intracellular iron homeostasis of erythroblasts

Blood ◽

10.1182/blood-2011-01-330241 ◽

2011 ◽

Vol 118 (10) ◽

pp. 2868-2877 ◽

Cited By ~ 53

Author(s):

De-Liang Zhang ◽

Thomas Senecal ◽

Manik C. Ghosh ◽

Hayden Ollivierre-Wilson ◽

Tiffany Tu ◽

...

Keyword(s):

Iron Deficiency ◽

Iron Homeostasis ◽

Fine Tuning ◽

Deficiency Anemia ◽

Iron Release ◽

Intracellular Iron ◽

Subsequent Increase ◽

A Cell ◽

Export Protein

Abstract The iron-regulatory hormone, hepcidin, regulates systemic iron homeostasis by interacting with the iron export protein ferroportin (FPN1) to adjust iron absorption in enterocytes, iron recycling through reticuloendothelial macrophages, and iron release from storage in hepatocytes. We previously demonstrated that FPN1 was highly expressed in erythroblasts, a cell type that consumes most of the serum iron for use in hemoglobin synthesis. Herein, we have demonstrated that FPN1 localizes to the plasma membrane of erythroblasts, and hepcidin treatment leads to decreased expression of FPN1 and a subsequent increase in intracellular iron concentrations in both erythroblast cell lines and primary erythroblasts. Moreover, injection of exogenous hepcidin decreased FPN1 expression in BM erythroblasts in vivo, whereas iron depletion and associated hepcidin reduction led to increased FPN1 expression in erythroblasts. Taken together, hepcidin decreased FPN1 expression and increased intracellular iron availability of erythroblasts. We hypothesize that FPN1 expression in erythroblasts allows fine-tuning of systemic iron utilization to ensure that erythropoiesis is partially suppressed when nonerythropoietic tissues risk developing iron deficiency. Our results may explain why iron deficiency anemia is the most pronounced early manifestation of mammalian iron deficiency.

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Erythroid Growth Differentiation Factor 15 and Ferroportin Expression During Gestational Iron Deficiency Anemia

Blood ◽

10.1182/blood.v118.21.5286.5286 ◽

2011 ◽

Vol 118 (21) ◽

pp. 5286-5286

Author(s):

Rekha Athiyarath ◽

Kalaiselvi Sakthivel ◽

Vinod J Abraham ◽

Daisy Singh ◽

Alok Srivastava ◽

...

Keyword(s):

Gene Expression ◽

Iron Deficiency ◽

Pregnant Women ◽

Iron Deficiency Anemia ◽

Iron Homeostasis ◽

Iron Absorption ◽

Deficiency Anemia ◽

Protein Levels ◽

In Pregnancy

Abstract Abstract 5286 Iron homeostasis during pregnancy is modulated to meet the increased iron needs but how this is achieved is not very clear. Growth Differentiation Factor (GDF15) produced by the expanded erythroid compartment in β thalassemia has been shown to increase iron absorption by suppressing hepcidin. GDF15 is also highly expressed in the placenta and increasing levels of GDF15 are seen with advancing gestational age of pregnancy. But the role of GDF15 in iron homeostasis in pregnancy has not been elucidated till date. Ferroportin (FPN) is the only known protein involved in iron export and it is the target of hepcidin, the central regulator of iron homeostasis. In this study we analyzed the expression of GDF15 and FPN in pregnant women with iron deficiency anemia. Fourteen pregnant women with proven iron deficiency anemia (IDAP) [Hb<11g/dL and Ferritin <12ng/ul] and thirteen healthy subjects as controls (NC) were enrolled as part of an ongoing study. Serum GDF15 and hepcidin levels were measured by ELISA kits from R&D systems and Bachem, UK respectively. Reticulocytes were isolated and total RNA was purified using Trizol. GDF15 and FPN transcripts were quantified using Taqman Gene expression assays using GAPDH as an internal control. Gene expression values were calculated on the basis of the 2-ΔΔCt method. The mean age of the pregnant women was 22.5±2.5 years. The median ferritin in IDAP was 1.4 and ranged from 0.2 to 8.3 ng/ml. The hepcidin levels were very low [<2ng/ml] in IDAP. Serum GDF15 levels in IDAP was significantly higher as compared to controls [IDAP-3333.71±409 pg/ml vs. NC-309.7±127.0 pg/ml; p=0.000]. Reticulocyte GDF15 mRNA expression was significantly lower [IDAP-25.09 (1.28–239.8) vs. NC-910.4 (0.28–1962); p=0.004] and FPN expression was significantly higher in pregnancy [IDAP-209.8 (48.33–1201) vs. NC-77.96(17.21–281.3); p=0.001] than in the controls. GDF15 mRNA as well as serum GDF15 levels significantly correlated with FPN expression in IDAP [RNA r=0.895; p=0.000; Protein r=0.555, p=0.049] Eight patients were followed up after 8 weeks of supplementation and there was no significant change in the serum GDF15 concentration (3235±468.26pg/ml; p=1.000). However their serum ferritin and hepcidin levels were significantly higher [Ferritin-11.60 (9.80–21.30), p=0.0021; Hepcidin-17.86(0.29–38.50), p=0.015]. There was no significant correlation between GDF15 protein levels and hepcidin (r=0.429, p=0.354). Molecular mechanisms of iron homeostasis in pregnancy are poorly understood. IDAP had very low hepcidin levels which normalized after iron stores were replenished. Elevated GDF15 protein levels in IDAP inspite of low reticulocyte expression indicate that erythroid contribution is minimal and placenta is the main source of GDF15. The significant correlation between GDF15 (mRNA and protein) with FPN expression and absence of correlation with hepcidin levels indicate a possible role for GDF15 in iron homeostasis in pregnancy. These findings has to be validated and the role of GDF15 in modulating FPN and there by iron absorption has to be further elucidated. Disclosures: No relevant conflicts of interest to declare.

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CBIO-10. REDUCED IRON EXPORT FUNCTIONS IN A CELL INTRINSIC MANNER TO DRIVE GLIOBLASTOMA GROWTH

Neuro-Oncology ◽

10.1093/neuonc/noaa215.070 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii17-ii17

Author(s):

Katie Troike ◽

Erin Mulkearns-Hubert ◽

Daniel Silver ◽

James Connor ◽

Justin Lathia

Keyword(s):

Tumor Cells ◽

Iron Uptake ◽

Iron Homeostasis ◽

Iron Status ◽

Tumor Grade ◽

Hfe Gene ◽

Iron Release ◽

Female Patients ◽

Cellular Iron

Abstract Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is characterized by invasive growth and poor prognosis. Iron is a critical regulator of many cellular processes, and GBM tumor cells have been shown to modulate expression of iron-associated proteins to enhance iron uptake from the surrounding microenvironment, driving tumor initiation and growth. While iron uptake has been the central focus of previous investigations, additional mechanisms of iron regulation, such as compensatory iron efflux, have not been explored in the context of GBM. The hemochromatosis (HFE) gene encodes a transmembrane glycoprotein that aids in iron homeostasis by limiting cellular iron release, resulting in a sequestration phenotype. We find that HFE is upregulated in GBM tumors compared to non-tumor brain and that expression of HFE increases with tumor grade. Furthermore, HFE mRNA expression is associated with significantly reduced survival specifically in female patients with GBM. Based on these findings, we hypothesize that GBM tumor cells upregulate HFE expression to augment cellular iron loading and drive proliferation, ultimately leading to reduced survival of female patients. To test this hypothesis, we generated Hfe knockdown and overexpressing mouse glioma cell lines. We observed significant alterations in the expression of several iron handling genes with Hfe knockdown or overexpression, suggesting global disruption of iron homeostasis. Additionally, we show that knockdown of Hfe in these cells increases apoptosis and leads to a significant impairment of tumor growth in vivo. These findings support the hypothesis that Hfe is a critical regulator of cellular iron status and contributes to tumor aggression. Future work will include further exploration of the mechanisms that contribute to these phenotypes as well as interactions with the tumor microenvironment. Elucidating the mechanisms by which iron effulx contributes to GBM may inform the development of next-generation targeted therapies.

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