Progress in Understanding Ferroptosis and Challenges in Its Targeting for Therapeutic Benefit

Zou, Yilong; Schreiber, Stuart L.

doi:10.1016/j.chembiol.2020.03.015

Cited by 88 publications

(59 citation statements)

References 118 publications

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“…More importantly, erastin, a more potent inhibitor of system xc-, has been shown to improve the anticancer activity of traditional chemotherapy drugs (e.g., docetaxel, cisplatin, and temozolomide) in several cancer cells [ 168 – 170 ]. Besides its promising role for cancer therapy, ferroptosis is also implicated in multiple forms of tissue damage, including ischemia/reperfusion injury [ 171 ], traumatic injury [ 172 ], and neurodegeneration [ 173 , 174 ].…”

Section: Regulation Of Iron Metabolism For Antitumor Immunitymentioning

confidence: 99%

Crosstalk between Macrophages, T Cells, and Iron Metabolism in Tumor Microenvironment

Shen

Zhou

et al. 2021

Oxidative Medicine and Cellular Longevity

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Leukocytes, including macrophages and T cells, represent key players in the human immune system, which plays a considerable role in the development and progression of tumors by immune surveillance or immune escape. Boosting the recruitment of leukocytes into the tumor microenvironment and promoting their antitumor responses have been hot areas of research in recent years. Although immunotherapy has manifested a certain level of success in some malignancies, the overall effectiveness is far from satisfactory. Iron is an essential trace element required in multiple, normal cellular processes, such as DNA synthesis and repair, cellular respiration, metabolism, and signaling, while dysregulated iron metabolism has been declared one of the metabolic hallmarks of malignant cancer cells. Furthermore, iron is implicated in the modulation of innate and adaptive immune responses, and elucidating the targeted regulation of iron metabolism may have the potential to benefit antitumor immunity and cancer treatment. In the present review, we briefly summarize the roles of leukocytes and iron metabolism in tumorigenesis, as well as their crosstalk in the tumor microenvironment. The combination of immunotherapy with targeted regulation of iron and iron-dependent regulated cell death (ferroptosis) may be a focus of future research.

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Section: Regulation Of Iron Metabolism For Antitumor Immunitymentioning

confidence: 99%

Crosstalk between Macrophages, T Cells, and Iron Metabolism in Tumor Microenvironment

Shen

Zhou

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…Ferroptosis is an iron-dependent cell-death modality driven by oxidative phospholipid damage and has been implicated in a number of diseases [18,19]. In our study, we investigated whether ferroptosis participated in the pathological progression of HDM induced asthma.…”

Section: Discussionmentioning

confidence: 99%

Environmental Allergens House Dust Mites-induced Asthma Causes Ferroptosis in the Lungs

Tang

Dong

Teng

et al. 2021

Preprint

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Background: Studies have indicated that allergens such as house dust mites (HDM) in the environment could induce allergic asthma. Ferroptosis is a newly discovered regulatory cell death characterized by aberrant lipid peroxidation and accumulation of reactive oxygen species (ROS) in cells. However, whether ferroptosis participates in the pathological progress of asthma remains to be elucidated. In this study, we used a HDM-induced mouse asthma model to determine the effect of HDM exposure on allergic asthma and the underlying mechanisms. Methods: Female BALB/c mice were intranasally exposed to HDM to induce allergic asthma. Airway hyperresponsiveness (AHR), lung inflammation and mucus secretion, IgE and cytokine levels as well as inflammatory cell counts in bronchalveolar lavage fluid (BALF) were investigated. In addition, the morphological changes of mitochondria, ROS, glutathione (GSH) levels and changes in ferroptosis pathway proteins in the lung were also determined. Results: HDM exposure increased AHR significantly, and enhanced inflammatory cell infiltration and mucus secretion around the airways. Furthermore, elevated IgE level in BALF, lung eosinophilia, and a concomitant increase in IL-13 and IL-5 in BALF were observed. HDM inhalation increased ROS and decreased GSH level in the lung. HDM inhalation induced dysmorphic small mitochondria with decreased crista, as well as condensed, ruptured outer membranes. Western blot analysis demonstrated that activity of glutathione peroxidase 4 (GPX4) and catalytic subunit solute carrier family 7 member 11 (SLC7A11) decreased significantly, and protein expression of acyl-CoA synthetase long-chain family member 4 (ACSL4) and 15 Lipoxygenase 1 (15-LO1) upregulated prominently compared with mice in normal control group. Conclusions: These in all indicated that the AHR, airway inflammation, lipid peroxidation and ROS level increased in HDM-induced asthma, and HDM inhalation caused ferroptosis in the lungs, which helped to form a better understanding of the pathogenesis of allergic asthma and targeted treatment strategies.

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“…Since 2012, when it was proposed, the concept of ferroptosis as a distinct form of cell death driven by the iron-dependent lipid peroxidation underwent impressive development. The mechanistic details of ferroptosis and its contribution to redox biology and disease have been rapidly clarified [ 10 , 76 , 77 ]. The involvement of ferroptotic pathways in diverse pathologies, such as tumors, neurodegeneration, stroke, ischemia-reperfusion injury among others, in combination with the successful development of chemical tools to manipulate lipid peroxidation, justifies the expectations of a strong clinical impact.…”

Section: Discussionmentioning

confidence: 99%

“…The involvement of ferroptotic pathways in diverse pathologies, such as tumors, neurodegeneration, stroke, ischemia-reperfusion injury among others, in combination with the successful development of chemical tools to manipulate lipid peroxidation, justifies the expectations of a strong clinical impact. However, a number of mechanistic questions and therapeutic challenges remains [ 77 ]. One of the remaining issues is the comprehensive understanding of the cellular states determining susceptibility to ferroptosis.…”

Section: Discussionmentioning

confidence: 99%

Ferroptosis-Related Flavoproteins: Their Function and Stability

Vabulas

2021

IJMS

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Ferroptosis has been described recently as an iron-dependent cell death driven by peroxidation of membrane lipids. It is involved in the pathogenesis of a number of diverse diseases. From the other side, the induction of ferroptosis can be used to kill tumor cells as a novel therapeutic approach. Because of the broad clinical relevance, a comprehensive understanding of the ferroptosis-controlling protein network is necessary. Noteworthy, several proteins from this network are flavoenzymes. This review is an attempt to present the ferroptosis-related flavoproteins in light of their involvement in anti-ferroptotic and pro-ferroptotic roles. When available, the data on the structural stability of mutants and cofactor-free apoenzymes are discussed. The stability of the flavoproteins could be an important component of the cellular death processes.

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Progress in Understanding Ferroptosis and Challenges in Its Targeting for Therapeutic Benefit

Cited by 88 publications

References 118 publications

Crosstalk between Macrophages, T Cells, and Iron Metabolism in Tumor Microenvironment

Crosstalk between Macrophages, T Cells, and Iron Metabolism in Tumor Microenvironment

Environmental Allergens House Dust Mites-induced Asthma Causes Ferroptosis in the Lungs

Ferroptosis-Related Flavoproteins: Their Function and Stability

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