Ferroptosis Signaling and Regulators in Atherosclerosis

Atherosclerosis (AS) is a major cause of cardiovascular diseases such as coronary heart disease, heart failure and stroke. Abnormal lipid metabolism, oxidative stress and inflammation are the main features of AS. Ferroptosis is an iron-driven programmed cell death characterized by lipid peroxidation, which have been proved to participate in the development and progression of AS by different signal pathways. NRF2-Keap1 pathway decreases ferroptosis associated with AS by maintaining cellular iron homeostasis, increasing the production glutathione, GPX4 and NADPH. The p53 plays different roles in ferroptosis at different stages of AS in a transcription-dependent and transcription- independent manner. The Hippo pathway is involved in progression of AS, which has been proved the activation of ferroptosis. Other transcription factors, such as ATF3, ATF4, STAT3, also involved in the occurrence of ferroptosis and AS. Certain proteins or enzymes also have a regulatory role in AS and ferroptosis. In this paper, we review the mechanism of ferroptosis and its important role in AS in an attempt to find a new relationship between ferroptosis and AS and provide new ideas for the future treatment of AS.

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Vitamin D-Mediated Anti-cancer Activity Involves Iron Homeostatic Balance Disruption and Oxidative Stress Induction in Breast Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.766978 ◽

2021 ◽

Vol 9 ◽

Author(s):

Khuloud Bajbouj ◽

Lina Sahnoon ◽

Jasmin Shafarin ◽

Abeer Al-Ali ◽

Jibran Sualeh Muhammad ◽

...

Keyword(s):

Breast Cancer ◽

Oxidative Stress ◽

Vitamin D ◽

Breast Cancer Cells ◽

Iron Homeostasis ◽

Stress Induction ◽

Protein Levels ◽

Cellular Iron ◽

Anti Cancer ◽

Cellular Iron Homeostasis

Background: Vitamin D deficiency associates with high risk of breast cancer (BRCA) and increased cellular iron. Vitamin D exerts some of its anti-cancer effects by regulating the expression of key iron regulatory genes (IRGs). The association between vitamin D and cellular iron content in BRCA remains ambiguous. Herein, we addressed whether vitamin D signaling exerts a role in cellular iron homeostasis thereby affecting survival of breast cancer cells.Methods: Expression profile of IRGs in vitamin D-treated breast cancer cells was analyzed using publicly available transcriptomic datasets. After treatment of BRCA cell lines MCF-7 and MDA-MB-231 with the active form of vitamin D, labile iron content, IRGs protein levels, oxidative stress, and cell survival were evaluated.Results: Bioinformatics analysis revealed several IRGs as well as cellular stress relates genes were differentially expressed in BRCA cells. Vitamin D treatment resulted in cellular iron depletion and differentially affected the expression of key IRGs protein levels. Vitamin D treatment exerted oxidative stress induction and alteration in the cellular redox balance by increasing the synthesis of key stress-related markers. Collectively, these effects resulted in a significant decrease in BRCA cell survival.Conclusion: These findings suggest that vitamin D disrupts cellular iron homeostasis leading to oxidative stress induction and cell death.

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Analysis of the biologic functions of H- and L-ferritins in HeLa cells by transfection with siRNAs and cDNAs: evidence for a proliferative role of L-ferritin

Blood ◽

10.1182/blood-2003-06-1842 ◽

2004 ◽

Vol 103 (6) ◽

pp. 2377-2383 ◽

Cited By ~ 93

Author(s):

Anna Cozzi ◽

Barbara Corsi ◽

Sonia Levi ◽

Paolo Santambrogio ◽

Giorgio Biasiotto ◽

...

Keyword(s):

Hela Cells ◽

Iron Homeostasis ◽

Background Level ◽

Iron Availability ◽

Small Interfering Rnas ◽

Down Regulation ◽

Independent Manner ◽

Cellular Iron ◽

Cell Clones ◽

Cellular Iron Homeostasis

Abstract We describe the use of small interfering RNAs (siRNAs) to down-regulate H- and L-ferritin levels in HeLa cells. siRNAs repressed H- and L-ferritin expression to about 20% to 25% of the background level in both stable and transient transfections. HeLa cells transfected with H- and L-ferritin cDNAs were analyzed in parallel to compare the effects of ferritin up- and down-regulation. We found that large modifications of L-ferritin levels did not affect iron availability in HeLa cells but positively affected cell proliferation rate in an iron-independent manner. The transient down-regulation of H-ferritin modified cellular iron availability and resistance to oxidative damage, as expected. In contrast, the stable suppression of H-ferritin in HeLa cell clones transfected with siRNAs did not increase cellular iron availability but made cells less resistant to iron supplementation and chelation. The results indicate that L-ferritin has no direct effects on cellular iron homeostasis in HeLa cells, while it has new, iron-unrelated functions. In addition, they suggest that H-ferritin function is to act as an iron buffer.

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Cellular Iron Homeostasis and Therapeutic Implications of Iron Chelators in Cancer

Current Pharmaceutical Biotechnology ◽

10.2174/138920101512141202111915 ◽

2014 ◽

Vol 15 (12) ◽

pp. 1125-1140 ◽

Cited By ~ 15

Author(s):

Mohsin Raza ◽

Sankalpa Chakraborty ◽

Monjoy Choudhury ◽

Prahlad Ghosh ◽

Alo Nag

Keyword(s):

Iron Homeostasis ◽

Iron Chelators ◽

Therapeutic Implications ◽

Cellular Iron ◽

Cellular Iron Homeostasis

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Biochemistry of mammalian ferritins in the regulation of cellular iron homeostasis and oxidative responses

Science China Life Sciences ◽

10.1007/s11427-020-1795-4 ◽

2020 ◽

Author(s):

Jianlin Zhang ◽

Xuehui Chen ◽

Juanji Hong ◽

Aifa Tang ◽

Yang Liu ◽

...

Keyword(s):

Iron Homeostasis ◽

Cellular Iron ◽

Cellular Iron Homeostasis ◽

Oxidative Responses

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IRONOMYCIN KILLS DIFFUSE LARGE B‐CELL LYMPHOMA CELLS BY TARGETING CELLULAR IRON HOMEOSTASIS

Hematological Oncology ◽

10.1002/hon.79_2881 ◽

2021 ◽

Vol 39 (S2) ◽

Author(s):

J. Devin ◽

T. Cañeque ◽

Y.‐L. Lin ◽

L. Mondoulet ◽

J.‐L. Veyrune ◽

...

Keyword(s):

B Cell ◽

Iron Homeostasis ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Lymphoma Cells ◽

Cellular Iron ◽

Large B Cell Lymphoma ◽

Cellular Iron Homeostasis ◽

Large B Cell

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Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis

Blood ◽

10.1182/blood-2004-07-2722 ◽

2005 ◽

Vol 105 (5) ◽

pp. 2161-2167 ◽

Cited By ~ 97

Author(s):

Guangjun Nie ◽

Alex D. Sheftel ◽

Sangwon F. Kim ◽

Prem Ponka

Keyword(s):

Iron Homeostasis ◽

Rna Binding ◽

Binding Activity ◽

Intracellular Iron ◽

Free Radical Damage ◽

Iron Regulatory Proteins ◽

Cellular Iron ◽

Cellular Iron Uptake ◽

A Cell ◽

Cellular Iron Homeostasis

AbstractCytosolic ferritin sequesters and stores iron and, consequently, protects cells against iron-mediated free radical damage. However, the function of the newly discovered mitochondrial ferritin (MtFt) is unknown. To examine the role of MtFt in cellular iron metabolism, we established a cell line that stably overexpresses mouse MtFt under the control of a tetracycline-responsive promoter. The overexpression of MtFt caused a dose-dependent iron deficiency in the cytosol that was revealed by increased RNA-binding activity of iron regulatory proteins (IRPs) along with an increase in transferrin receptor levels and decrease in cytosolic ferritin. Consequently, the induction of MtFt resulted in a dramatic increase in cellular iron uptake from transferrin, most of which was incorporated into MtFt. The induction of MtFt caused a shift of iron from cytosolic ferritin to MtFt. In addition, iron inserted into MtFt was less available for chelation than that in cytosolic ferritin and the expression of MtFt was associated with decreased mitochondrial and cytosolic aconitase activities, the latter being consistent with the increase in IRP-binding activity. In conclusion, our results indicate that overexpression of MtFt causes a dramatic change in intracellular iron homeostasis and that shunting iron to MtFt likely limits its availability for active iron proteins.

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