Emerging Mechanisms and Disease Relevance of Ferroptosis

doi:10.1016/j.tcb.2020.02.009

Trends in Cell Biology

Volume 30, Issue 6, June 2020, Pages 478-490

https://doi.org/10.1016/j.tcb.2020.02.009 Get rights and content

Highlights

There are three parallel pathways for defending against cell death by ferroptosis.
Iron availability is controlled by cellular iron import, storage, and efflux mechanisms.
Several tumor suppressor genes normally prevent tumor development by activating ferroptosis in developing tumor cells.
As cancers evolve to a more aggressive state, they become increasingly sensitive to ferroptosis.
The immune system uses ferroptosis as a means of eliminating cancer cells.

Cell death is an essential feature of development in multicellular organisms, a critical driver of degenerative diseases, and can be harnessed for treating some cancers. Understanding the mechanisms governing cell death is critical for addressing its role in disease. Similarly, metabolism is essential for normal energy and biomolecule production, and goes awry in many diseases. Metabolism and cell death are tightly linked in the phenomenon of ferroptosis, a form of regulated cell death driven by peroxidation of phospholipids. Glutathione peroxidase 4 (GPX4) uses glutathione to protect cells from ferroptosis by eliminating phospholipid peroxides. Recent data have revealed glutathione/GPX4-independent axes for suppressing ferroptosis, and insight into the regulation of iron and mitochondria in ferroptosis. Ferroptosis has recently been implicated in multiple diseases, and functions as a tumor suppression mechanism. Ferroptosis induction is a promising approach in treating several conditions, including neoplastic diseases. Here, we summarize these recent advances.

Section snippets

Ferroptosis Is a Recently Discovered Form of Cell Death That Is Controlled by Numerous Metabolic Pathways

Cells are the fundamental organizing unit of biological systems. The mechanisms governing the division, growth, proliferation, and death of cells are central to understanding the logic underlying the functioning of life on Earth, the possibility of life elsewhere in the universe, and the processes by which disease develops. Ferroptosis is a recently described form of cell death involving iron-dependent damage to membrane lipids; numerous metabolic pathways involving iron, lipids, and amino

Brief History of Ferroptosis

Cell death is critical for the normal development of multicellular organisms, and is aberrantly activated or suppressed in a large number of diseases [1]. Cell death was historically considered to be unregulated, until the 1950s, when the concept of ‘programmed cell death’ emerged, which led in subsequent decades to the discovery of apoptosis as a form of programmed cell death, along with expanding insight into its mechanisms of operation. For a time, apoptosis was synonymous with programmed

Ferroptosis Is Regulated by Numerous Pathways and Implicated in an Increasing Number of Diseases

Ferroptosis is a form of cell death first reported in 2012 [4], although many of the processes involved in ferroptosis had been observed in isolation decades earlier, but not integrated into a unified process [8]. The mechanisms governing ferroptosis that were elucidated in the first few years after it was discovered centered around cysteine and glutathione metabolism, and the ability of the phospholipid peroxidase GPX4 to prevent the accumulation of peroxidized lipids [9], which built on early

Regulation of Iron in Ferroptosis

Despite incorporating iron in the name, the role of and regulation of iron in ferroptosis only emerged recently. Initially, confusion surrounded as to whether the lipid peroxidation that drives ferroptosis was caused by the labile iron pool reacting with lipid peroxides to propagate these species in membranes, or whether iron-dependent enzymes might solely drive this peroxidation process. Studies from several laboratories revealed that iron-dependent lipoxygenases often initiate ferroptosis by

Lipid Peroxide Regulation

As noted earlier, the glutathione-dependent phospholipid peroxidase GPX4 was the first-discovered central inhibitor of ferroptosis [9]. GPX4 is a selenoprotein, implying that selenium availability impacts the sensitivity to ferroptosis. Indeed, delivery of selenium to cells or animals suppresses ferroptosis, including in a mouse model of intracerebral hemorrhage [26., 27., 28.].

A genetic screen for regulators of ferroptosis sensitivity revealed the surprising finding that the multidrug

Ferroptosis as a Tumor Suppression Mechanism

While illuminating the basic mechanisms by which ferroptosis operates is of value for understanding fundamental cell biology, determining the natural functions of ferroptosis will aid in understanding how and why this form of cell death emerged during evolution. Accumulating evidence indicates that ferroptotic cell death leads to tumor growth suppression. Nevertheless, it remains to be further defined whether ferroptosis acts as a critical barrier to cancer development. Inactivation of the p53

Ferroptosis Modulation as a Therapeutic Avenue

Although a definitive physiological function for ferroptosis has yet to be unambiguously demonstrated, the role of ferroptosis in human diseases has been established. A wealth of studies suggests that pharmacological modulation of this unique cell death modality, by either inhibiting it or stimulating it, may yield significant clinical benefit for certain diseases.

Concluding Remarks and Future Perspectives

The rapid expansion of our understanding of ferroptosis is due to the growing number of laboratories that are exploring the mechanisms and functions of this form of cell death. Given the recent advances, we know that there are at least three major pathways that control sensitivity of cells to ferroptosis: the glutathione–GPX4, NADPH–FSP1–CoQ₁₀, and GCH1–BH4 pathways. Moreover, it appears clear that ferroptosis contributes to both degenerative disease pathology and tumor suppression, and that

Acknowledgments

Research by the authors is supported by the National Institutes of Health (NIH) R01CA204232 (to X.J.), a Geoffrey Beene Cancer Research fund (to X.J.), a Functional Genomic Initiative fund (to X.J), the National Cancer Institute R35CA209896, P01CA087497 (to B.R.S.), and R01CA085533 and RO1CA224272 (to W.G), and the National institute of Neurological Disorders and Stroke R61NS109407 (to B.R.S.).

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Cited by (661)

Identification of key ferrotoposis-related therapeutic targets in icariin efficacy for postmenopausal osteoporosis treatment
2024, Pharmacological Research - Modern Chinese Medicine
Postmenopausal osteoporosis (PMOP) is a common disorder that threatens the health of postmenopausal women. Icariin (ICA), as a bioactive component extracted from the Chinese medicine Epimedium grandiflorum(Yinyanghuo), can reportedly relieve PMOP by reversing iron-overloaded bone loss. However, the detailed relationship between ferroptosis and icariin efficacy for PMOP treatment still needs further exploration.
The PMOP model rats were established by performing ovariectomy and further validated by Micro-CT scanning. Potential ferroptosis-related differentially expressed genes in PMOP and ICA efficacy were identified via bioinformatics analyses. Finally, hub genes were further verified via real-time quantitative PCR.
In this study, 126 ferroptosis-related differentially expressed genes (DE-FRGs) in PMOP were first screened out. Gene Ontology (GO) biological process and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of these genes were performed for the pursuit of further functional enrichment analysis. The protein-protein interaction (PPI) network was constructed to identify key modules within all the DE-FRGs. Then, DE-FRGs were further intersected with predicted target genes of ICA, and 11 genes were considered as potential icariin-regulated DE-FRGs in PMOP. After gene expression measurements of potential icariin-regulated DE-FRGs, five genes (PPARA, TGFB1, SRC, IL6, and SIRT1) were ultimately chosen as hub genes for ICA-regulated ferroptosis in PMOP treatment. Finally, the ROC curve and ceRNA network were established.
This study discovered potential ferroptosis-related therapeutic targets in ICA efficacy for PMOP treatment, which also contributes to the consideration of ICA as a novel therapy for PMOP.
Celastrol inhibits oligodendrocyte and neuron ferroptosis to promote spinal cord injury recovery
2024, Phytomedicine
Spinal cord injury (SCI) is a traumatic injury to the central nervous system and can cause lipid peroxidation in the spinal cord. Ferroptosis, an iron-dependent programmed cell death, plays a key role in the pathophysiology progression of SCI. Celastrol, a widely used antioxidant drug, has potential therapeutic value for nervous system.
To investigate whether celastrol can be a reliable candidate for ferroptosis inhibitor and the molecular mechanism of celastrol in repairing SCI by inhibiting ferroptosis.
First, a rat SCI model was constructed, and the recovery of motor function was observed after treatment with celastrol. The regulatory effect of celastrol on ferroptosis pathway Nrf2-xCT-GPX4 was detected by Western blot and immunofluorescence. Finally, the ferroptosis model of neurons and oligodendrocytes was constructed in vitro to further verify the mechanism of inhibiting ferroptosis by celastrol.
Our results demonstrated that celastrol promoted the recovery of spinal cord tissue and motor function in SCI rats. Further in vitro and in vivo studies showed that celastrol significantly inhibited ferroptosis in neurons and oligodendrocytes and reduced the accumulation of ROS. Finally, we found that celastrol could inhibit ferroptosis by up-regulating the Nrf2-xCT-GPX4 axis to repair SCI.
Celastrol effectively inhibits ferroptosis after SCI by upregulating the Nrf2-xCT-GPX4 axis, reducing the production of lipid ROS, protecting the survival of neurons and oligodendrocytes, and improving the functional recovery.
Coenzyme Q10 in atherosclerosis
2024, European Journal of Pharmacology
Atherosclerotic disease is a chronic disease that predominantly affects the elderly and is the most common cause of cardiovascular death worldwide. Atherosclerosis is closely related to processes such as abnormal lipid transport and metabolism, impaired endothelial function, inflammation, and oxidative stress. Coenzyme Q10 (CoQ10) is a key component of complex Ⅰ in the electron transport chain and an important endogenous antioxidant that may play a role in decelerating the progression of atherosclerosis. Here, the different forms of CoQ10 presence in the electron transport chain are reviewed, as well as its physiological role in regulating processes such as oxidative stress, inflammatory response, lipid metabolism and cellular autophagy. It was also found that CoQ10 plays beneficial effects in atherosclerosis by mitigating lipid transportation, endothelial inflammation, metabolic abnormalities, and thrombotic processes from the perspectives of molecular mechanisms, animal experiments, and clinical evidence. Besides, the combined use of CoQ10 with other drugs has better synergistic therapeutic effects. It seems reasonable to suggest that CoQ10 could be used in the treatment of atherosclerotic cardiovascular diseases while more basic and clinical studies are needed.
Vitamin B<inf>6</inf> alleviates chronic sleep deprivation-induced hippocampal ferroptosis through CBS/GSH/GPX4 pathway
2024, Biomedicine and Pharmacotherapy
Several studies have found that sleep deprivation (SD) can lead to neuronal ferroptosis and affect hippocampal function. However, there are currently no effective interventions. Vitamin B₆ is a co-factor for key enzymes in the transsulfuration pathway which is critical for maintaining cell growth in the presence of cysteine deprivation. The results showed that SD inhibited cystine-glutamate antiporter light chain subunit xCT protein expression and caused cysteine deficiency, which reduced the synthesis of the glutathione (GSH) to trigger neuronal ferroptosis. Nissl staining further revealed significant neuronal loss and shrinkage in the CA1 and CA3 regions of the hippocampus in SD mice. Typical ferroptotic indicators characterized by lipid peroxidation and iron accumulation were showed in the hippocampus after sleep deprivation. As expected, vitamin B₆ could alleviate hippocampal ferroptosis by upregulating the expression of cystathionine beta-synthase (CBS) in the transsulfuration pathway, thereby replenishing the intracellular deficient GSH and restoring the expression of GPX4. Similar anti-ferroptotic effects of vitamin B₆ were demonstrated in HT-22 cells treated with ferroptosis activator erastin. Furthermore, vitamin B₆ had no inhibitory effect on erastin-induced ferroptosis in CBS-knockout HT22 cells. Our findings suggested chronic sleep deprivation caused hippocampal ferroptosis by disrupting the cyst(e)ine/GSH/GPX4 axis. Vitamin B₆ alleviated sleep deprivation-induced ferroptosis by enhancing CBS expression in the transsulfuration pathway.
GPX4, ferroptosis, and diseases
2024, Biomedicine and Pharmacotherapy
GPX4 (Glutathione peroxidase 4) serves as a crucial intracellular regulatory factor, participating in various physiological processes and playing a significant role in maintaining the redox homeostasis within the body. Ferroptosis, a form of iron-dependent non-apoptotic cell death, has gained considerable attention in recent years due to its involvement in multiple pathological processes. GPX4 is closely associated with ferroptosis and functions as the primary inhibitor of this process. Together, GPX4 and ferroptosis contribute to the pathophysiology of several diseases, including sepsis, nervous system diseases, ischemia reperfusion injury, cardiovascular diseases, and cancer. This review comprehensively explores the regulatory roles and impacts of GPX4 and ferroptosis in the development and progression of these diseases, with the aim of providing insights for identifying potential therapeutic strategies in the future.
Emerging regulatory mechanisms in cardiovascular disease: Ferroptosis
2024, Biomedicine and Pharmacotherapy
Ferroptosis, distinct from apoptosis, necrosis, autophagy, and other types of cell death, is a novel iron-dependent regulated cell death characterized by the accumulation of lipid peroxides and redox imbalance with distinct morphological, biochemical, and genetic features. Dysregulation of iron homeostasis, the disruption of antioxidative stress pathways and lipid peroxidation are crucial in ferroptosis. Ferroptosis is involved in the pathogenesis of several cardiovascular diseases, including atherosclerosis, cardiomyopathy, myocardial infarction, ischemia-reperfusion injury, abdominal aortic aneurysm, aortic dissection, and heart failure. Therefore, a comprehensive understanding of the mechanisms that regulate ferroptosis in cardiovascular diseases will enhance the prevention and treatment of these diseases. This review discusses the latest findings on the molecular mechanisms of ferroptosis and its regulation in cardiovascular diseases, the application of ferroptosis modulators in cardiovascular diseases, and the role of traditional Chinese medicines in ferroptosis regulation to provide a comprehensive understanding of the pathogenesis of cardiovascular diseases and identify new prevention and treatment options.

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Trends in Cell Biology

ReviewEmerging Mechanisms and Disease Relevance of Ferroptosis

Highlights

Section snippets

Ferroptosis Is a Recently Discovered Form of Cell Death That Is Controlled by Numerous Metabolic Pathways

Brief History of Ferroptosis

Ferroptosis Is Regulated by Numerous Pathways and Implicated in an Increasing Number of Diseases

Regulation of Iron in Ferroptosis

Lipid Peroxide Regulation

Ferroptosis as a Tumor Suppression Mechanism

Ferroptosis Modulation as a Therapeutic Avenue

Concluding Remarks and Future Perspectives

Acknowledgments

Cell

Cancer Cell

Cell

Chem. Biol.

Free Radic. Biol. Med.

Cell

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Arch. Biochem. Biophys.

Cell Metab.

Free Radic. Biol. Med.

Cell

Mol. Cell

Cell Rep.

Cancer Cell

FEBS Lett.

Cancer Lett.

Trends Mol. Med.

Trends Biochem. Sci.

Cell

J Invest Dermatol

Biochim. Biophys. Acta

J Invest Dermatol

Toxicol. Lett.

Free Radic. Biol. Med.

Behav. Brain Res.

J. Biol. Chem.

Cell Metab.

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Cell Death Differ.

RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels

Nature

Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis

eLife

Nutrition needs of mammalian cells in tissue culture

Science

The specific amino acid requirements of a human carcinoma cell (Stain HeLa) in tissue culture

J. Exp. Med.

Acetaminophen-induced hepatic necrosis. 3. Cytochrome P-450-mediated covalent binding in vitro

J. Pharmacol. Exp. Ther.

Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione

J. Pharmacol. Exp. Ther.

Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism

J. Pharmacol. Exp. Ther.

Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo

J. Pharmacol. Exp. Ther.

Resolving the role of lipoxygenases in the initiation and execution of ferroptosis

ACS Cent. Sci.

PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals

Cell

Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis

Nat. Chem. Biol.

Autophagy promotes ferroptosis by degradation of ferritin

Autophagy

Ferroptosis is an autophagic cell death process

Cell Res.

Prominin2 drives ferroptosis resistance by stimulating iron export

Dev. Cell

Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke

Cell

Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis

Cell

A genome-wide haploid genetic screen identifies regulators of glutathione abundance and ferroptosis sensitivity

Cell Rep.

Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis

Nat. Chem. Biol.

FSP1 is a glutathione-independent ferroptosis suppressor

Review
Emerging Mechanisms and Disease Relevance of Ferroptosis