Revealing the Ferroptotic Phenotype of Medulloblastoma.

The interaction of iron and oxygen is an integral part of the development of life on Earth. Nonetheless, this unique chemistry continues to fascinate and puzzle, leading to new biological ventures. In 2012, a Columbia University group recognized this interaction as a central event leading to a new type of regulated cell death named "ferroptosis." The major feature of ferroptosis is the accumulation of lipid hydroperoxides due to (1) dysfunctional antioxidant defense and/or (2) overwhelming oxidative stress, which most frequently coincides with increased content of free labile iron in the cell. This is normally prevented by the canonical anti-ferroptotic axis comprising the cystine transporter xCT, glutathione (GSH), and GSH peroxidase 4 (GPx4). Since ferroptosis is not a programmed type of cell death, it does not involve signaling pathways characteristic of apoptosis. The most common way to prove this type of cell death is by using lipophilic antioxidants (vitamin E, ferrostatin-1, etc.) to prevent it. These molecules can approach and detoxify oxidative damage in the plasma membrane. Another important aspect in revealing the ferroptotic phenotype is detecting the preceding accumulation of lipid hydroperoxides, for which the specific dye BODIPY C11 is used. The present manuscript will show how ferroptosis can be induced in wild-type medulloblastoma cells by using different inducers: erastin, RSL3, and iron-donor. Similarly, the xCT-KO cells that grow in the presence of NAC, and which undergo ferroptosis once NAC is removed, will be used. The characteristic "bubbling" phenotype is visible under the light microscope within 12-16 h from the moment of ferroptosis triggering. Furthermore, BODIPY C11 staining followed by FACS analysis to show the accumulation of lipid hydroperoxides and consequent cell death using the PI staining method will be used. To prove the ferroptotic nature of cell death, ferrostatin-1 will be used as a specific ferroptosis-preventing agent.

[Characteristics of lipid peroxidation processes and factors of the antioxidant defense system in chronic rhinitis]. / Kharakteristika protsessov lipoperoksidatsii i faktorov sistemy antioksidantnoi zashchity pri khronicheskom rinite.

The problem of chronic rhinitis (CR) remains unresolved in the world, while it has a negative impact on the quality of life of patients. Chronic forms of rhinitis suffer from 10-20% of the population, and its symptoms in epidemiological studies are noted in 40% of respondents. One of the leading mechanisms of disease occurrence is oxidative stress. OBJECTIVE: To study the state of the processes of lipid peroxidation and antioxidant protection in various types of chronic rhinitis. MATERIAL AND METHODS: The study included 50 patients with CR, of which 21 were with chronic allergic rhinitis (CALR), 20 with chronic vasomotor rhinitis (CVR), 9 with chronic atrophic rhinitis (CAR). The control group was represented by 50 practically healthy volunteers with no otorhinolaryngological complaints. The indicators of the LPO-AOD system in erythrocytes were evaluated by spectrophotometric methods. Statistical data processing was carried out using the Statistica 7.0 software package (StatSoft, USA). RESULTS: In all patients with CR in the blood erythrocytes, an increase in the level of malondialdehyde (MDA), a decrease in the activity of superoxide dismutase (SOD), catalase (CAT) relative to the control group was found. With CAR, the most pronounced changes are determined, with CVR - minimal. In patients with CR, lipid peroxidation is activated, MDA increases by 1.29 times, by 1.37 times with CAR, and by 1.31 times with CALR relative to normal values. The activity of the antioxidant system decreases, which reflects the classical variant of inhibition of antioxidant enzymes: SOD is reduced by 1.08 times in CAR, by 1.07 times in CALR, and 1.04 times in CVR, CAT in CAR is reduced by 1.02 times; CALR by 1.02 times, with CVR by 1.01 times. The coefficient of oxidative stress with CVR is 1.36, with CAR is 1.5, with CALR is 1.42. CONCLUSION: In CR, the predominance of pro-oxidant processes over antioxidant ones is revealed, a slight oxidative stress is detected, probably due to the presence of hypoxia and intoxication syndrome. An in-depth study of lipid peroxidation processes and factors of the antioxidant defense system, depending on the CR phenotype, can be used to correct therapy and prevent exacerbations, as well as markers of progression and prognosis of chronic rhinitis.

A tangible method to assess native ferroptosis suppressor activity.

Ferroptosis, a regulated cell death hallmarked by unrestrained lipid peroxidation, plays a pivotal role in the pathophysiology of various diseases, making it a promising therapeutic target. Glutathione peroxidase 4 (GPX4) prevents ferroptosis by reducing (phospho)lipid hydroperoxides, yet evaluation of its actual activity has remained arduous. Here, we present a tangible method using affinity-purified GPX4 to capture a snapshot of its native activity. Next to measuring GPX4 activity, this improved method allows for the investigation of mutational GPX4 activity, exemplified by the GPX4U46C mutant lacking selenocysteine at its active site, as well as the evaluation of GPX4 inhibitors, such as RSL3, as a showcase. Furthermore, we apply this method to the second ferroptosis guardian, ferroptosis suppressor protein 1, to validate the newly identified ferroptosis inhibitor WIN62577. Together, these methods open up opportunities for evaluating alternative ferroptosis suppression mechanisms.

PHLDA2-mediated phosphatidic acid peroxidation triggers a distinct ferroptotic response during tumor suppression.

Although the role of ferroptosis in killing tumor cells is well established, recent studies indicate that ferroptosis inducers also sabotage anti-tumor immunity by killing neutrophils and thus unexpectedly stimulate tumor growth, raising a serious issue about whether ferroptosis effectively suppresses tumor development in vivo. Through genome-wide CRISPR-Cas9 screenings, we discover a pleckstrin homology-like domain family A member 2 (PHLDA2)-mediated ferroptosis pathway that is neither ACSL4-dependent nor requires common ferroptosis inducers. PHLDA2-mediated ferroptosis acts through the peroxidation of phosphatidic acid (PA) upon high levels of reactive oxygen species (ROS). ROS-induced ferroptosis is critical for tumor growth in the absence of common ferroptosis inducers; strikingly, loss of PHLDA2 abrogates ROS-induced ferroptosis and promotes tumor growth but has no obvious effect in normal tissues in both immunodeficient and immunocompetent mouse tumor models. These data demonstrate that PHLDA2-mediated PA peroxidation triggers a distinct ferroptosis response critical for tumor suppression and reveal that PHLDA2-mediated ferroptosis occurs naturally in vivo without any treatment from ferroptosis inducers.

Songbirds avoid the oxidative stress costs of high blood glucose levels: a comparative study.

Chronically high blood glucose levels (hyperglycaemia) can compromise healthy ageing and lifespan at the individual level. Elevated oxidative stress can play a central role in hyperglycaemia-induced pathologies. Nevertheless, the lifespan of birds shows no species-level association with blood glucose. This suggests that the potential pathologies of high blood glucose levels can be avoided by adaptations in oxidative physiology at the macroevolutionary scale. However, this hypothesis remains unexplored. Here, we examined this hypothesis using comparative analyses controlled for phylogeny, allometry and fecundity based on data from 51 songbird species (681 individuals with blood glucose data and 1021 individuals with oxidative state data). We measured blood glucose at baseline and after stress stimulus and computed glucose stress reactivity as the magnitude of change between the two time points. We also measured three parameters of non-enzymatic antioxidants (uric acid, total antioxidants and glutathione) and a marker of oxidative lipid damage (malondialdehyde). We found no clear evidence for blood glucose concentration being correlated with either antioxidant or lipid damage levels at the macroevolutionary scale, as opposed to the hypothesis postulating that high blood glucose levels entail oxidative costs. The only exception was the moderate evidence for species with a stronger stress-induced increase in blood glucose concentration evolving moderately lower investment into antioxidant defence (uric acid and glutathione). Neither baseline nor stress-induced glucose levels were associated with oxidative physiology. Our findings support the hypothesis that birds evolved adaptations preventing the (glyc)oxidative costs of high blood glucose observed at the within-species level. Such adaptations may explain the decoupled evolution of glycaemia and lifespan in birds and possibly the paradoxical combination of long lifespan and high blood glucose levels relative to mammals.

Unraveling lipid peroxidation-mediated regulation of redox homeostasis for sustaining plant health.

Lipid peroxidation (LPO) is a complex process that, depending on the context, can either result in oxidative injury or promote redox homeostasis. LPO is a series of reactions in which polyunsaturated fatty acids are attacked by free radicals that result in the synthesis of lipid peroxides. LPO can alter membrane fluidity and operation and produce secondary products that amplify oxidative stress. LPO can activate cellular signaling pathways that promote antioxidant defense mechanisms that provide oxidative stress protection by elevating antioxidant enzyme action potentials. Enzymatic and nonenzymatic mechanisms tightly regulate LPO to prevent excessive LPO and its adverse consequences. This article emphasizes the dual nature of LPO as a mechanism that can both damage cells and regulate redox homeostasis. In addition, it also highlights the major enzymatic and nonenzymatic mechanisms that tightly regulate LPO to prevent excessive oxidative damage. More importantly, it emphasizes the importance of understanding the cellular and biochemical complexity of LPO for developing strategies targeting this process for efficient management of plant stress.

Arginine Expedites Erastin-Induced Ferroptosis through Fumarate.

Ferroptosis is a newly characterized form of programmed cell death. The fundamental biochemical feature of ferroptosis is the lethal accumulation of iron-catalyzed lipid peroxidation. It has gradually been recognized that ferroptosis is implicated in the pathogenesis of a variety of human diseases. Increasing evidence has shed light on ferroptosis regulation by amino acid metabolism. Herein, we report that arginine deprivation potently inhibits erastin-induced ferroptosis, but not RSL3-induced ferroptosis, in several types of mammalian cells. Arginine presence reduces the intracellular glutathione (GSH) level by sustaining the biosynthesis of fumarate, which functions as a reactive α,ß-unsaturated electrophilic metabolite and covalently binds to GSH to generate succinicGSH. siRNA-mediated knockdown of argininosuccinate lyase, the critical urea cycle enzyme directly catalyzing the biosynthesis of fumarate, significantly decreases cellular fumarate and thus relieves erastin-induced ferroptosis in the presence of arginine. Furthermore, fumarate is decreased during erastin exposure, suggesting that a protective mechanism exists to decelerate GSH depletion in response to pro-ferroptotic insult. Collectively, this study reveals the ferroptosis regulation by the arginine metabolism and expands the biochemical functionalities of arginine.

Mechanisms and regulations of ferroptosis.

Regulation of cell mortality for disease treatment has been the focus of research. Ferroptosis is an iron-dependent regulated cell death whose mechanism has been extensively studied since its discovery. A large number of studies have shown that regulation of ferroptosis brings new strategies for the treatment of various benign and malignant diseases. Iron excess and lipid peroxidation are its primary metabolic features. Therefore, genes involved in iron metabolism and lipid metabolism can regulate iron overload and lipid peroxidation through direct or indirect pathways, thereby regulating ferroptosis. In addition, glutathione (GSH) is the body's primary non-enzymatic antioxidants and plays a pivotal role in the struggle against lipid peroxidation. GSH functions as an auxiliary substance for glutathione peroxidase 4 (GPX4) to convert toxic lipid peroxides to their corresponding alcohols. Here, we reviewed the researches on the mechanism of ferroptosis in recent years, and comprehensively analyzed the mechanism and regulatory process of ferroptosis from iron metabolism and lipid metabolism, and then described in detail the metabolism of GPX4 and the main non-enzymatic antioxidant GSH in vivo.

Transcriptomic Profiling Identifies Ferroptosis-Related Gene Signatures in Ischemic Muscle Satellite Cells Affected by Peripheral Artery Disease-Brief Report.

BACKGROUND: We hypothesized that transcriptomic profiling of muscle satellite cells in peripheral artery disease (PAD) would identify damage-related pathways contributing to skeletal muscle myopathy. We identified a potential role for ferroptosis-a form of programmed lytic cell death by iron-mediated lipid peroxidation-as one such pathway. Ferroptosis promotes myopathy in ischemic cardiac muscle but has an unknown role in PAD. METHODS: Muscle satellite cells from donors with PAD were obtained during surgery. cDNA libraries were processed for single-cell RNA sequencing using the 10X Genomics platform. Protein expression was confirmed based on pathways inferred by transcriptomic analysis. RESULTS: Unsupervised cluster analysis of over 25 000 cells aggregated from 8 donor samples yielded distinct cell populations grouped by a shared unique transcriptional fingerprint. Quiescent cells were diminished in ischemic muscle while myofibroblasts and apoptotic cells were prominent. Differential gene expression demonstrated a surprising increase in genes associated with iron transport and oxidative stress and a decrease in GPX4 (glutathione peroxidase 4) in ischemic PAD-derived cells. Release of the danger signal HMGB1 (high mobility group box-1) correlated with ferroptotic markers including surface transferrin receptor and were higher in ischemia. Furthermore, lipid peroxidation in muscle satellite cells was modulated by ferrostatin, a ferroptosis inhibitor. Histology confirmed iron deposition and lipofuscin, an inducer of ferroptosis in PAD-affected muscle. CONCLUSIONS: This report presents a novel finding that genes known to be involved in ferroptosis are differentially expressed in human skeletal muscle affected by PAD. Targeting ferroptosis may be a novel therapeutic strategy to reduce PAD myopathy.

The ubiquitin-proteasome system links NADPH metabolism to ferroptosis.

Ferroptosis is the type of cell death arising from uncontrolled and excessive lipid peroxidation. NADPH is essential for ferroptosis regulation because it supplies reducing equivalents for antioxidant defense systems and contributes to the generation of reactive oxygen species. Moreover, NADPH level serves as a biomarker for predicting the sensitivity of cells to ferroptosis. The ubiquitin-proteasome system governs the stability of many ferroptosis effectors. Recent research has revealed MARCHF6, the endoplasmic reticulum ubiquitin ligase, as an unprecedented NADPH sensor in the ubiquitin system and a critical regulator of ferroptosis involved in tumorigenesis and fetal development. This review summarizes the current understanding of NADPH metabolism and the ubiquitin-proteasome system in regulating ferroptosis and highlights the emerging importance of MARCHF6 as a vital connector between NADPH metabolism and ferroptosis.

In situ and dynamic SERS monitoring of glutathione levels during cellular ferroptosis metabolism.

Ferroptosis is a non-apoptotic cell death regulated by iron-dependent lipid peroxidation. Glutathione (GSH), a key antioxidant against oxidative damage, is involved in one of the most important metabolic pathways of ferroptosis. Herein, an excellent plasmonic nanoprobe was developed for highly sensitive, in situ, dynamic real-time monitoring of intracellular GSH levels during ferroptosis. A nanoprobe was prepared by functionalizing gold nanoparticles (AuNPs) with the probe molecule crystal violet (CV). The fluctuation in the SERS signal intensity of CV via the competitive displacement reaction can be used to detect GSH. The advantages of the plasmonic nanoprobe including low-cost production techniques, outstanding stability and biocompatibility, high specificity and sensitivity towards GSH with a detection limit of 0.05 µM. It enables real-time dynamic monitoring of GSH levels in living cells during erastin-induced ferroptosis. This approach is expected to provide important theoretical support for elucidating the GSH-related ferroptosis metabolic mechanism and advancing our understanding of ferroptosis-based cancer therapy. Overview of the workflow of sensing principle for highly sensitive, in situ and dynamic tracking of intracellular GSH levels during drug-triggered ferroptosis process.

Stratifying Ferroptosis Sensitivity in Cells and Tissues with PALP.

Ferroptosis is emerging as a promising strategy for suppressing multiple types of human cancers. Rapid and accurate assessment of the relative sensitivity to ferroptosis in biological samples will accelerate the development of ferroptosis-targeted therapies. We previously demonstrated that photochemical activation of membrane lipid peroxidation (PALP) that uses high-power lasers to induce localized polyunsaturated fatty acyl (PUFA)-lipid peroxidation can efficiently report ferroptosis sensitivity in live cells and tissues in situ. Here, we describe the experimental details for PALP analysis, including preparation of tissue sections, preparation of fluorescent lipid peroxidation reporter, sample staining, lipid peroxidation induced by laser source, and data processing. We envision predicting the relative sensitivity to ferroptosis of cellular and tissue samples is potentially useful for basic research and clinical investigations.

Probing Lipid Peroxidation in Ferroptosis: Emphasizing the Utilization of C11-BODIPY-Based Protocols.

Ferroptosis is a form of regulated cell death that relies on iron and is characterized by the accumulation of lipid peroxides, resulting in oncotic cell swelling and eventual disruption of cellular membranes. Lipid peroxidation, a hallmark of ferroptosis, refers to the oxidative deterioration of lipids that contain carbon-carbon double bonds, particularly polyunsaturated fatty acids (PUFAs). Understanding the molecular mechanisms underlying the interplay between ferroptosis and lipid peroxidation and identifying reliable techniques for assessing lipid peroxidation levels are crucial for further advancements in this field of research. Various methods have been developed to detect lipid peroxidation levels, including C11-BODIPY (BODIPY™ 581/591 C11), liperfluo, 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), Click-iT LAA (linoleamide alkyne), and liquid chromatography-mass spectrometry (LC-MS)-based epilipidomics (redox lipidomics). Currently, one of the most commonly used and effective methods is the C11-BODIPY assay, which utilizes a fluorescent probe that selectively sensitizes lipid peroxidation in cell membranes. Incorporating advanced techniques such as flow cytometry and fluorescence microscopy with C11-BODIPY dye is essential for accurate assessment of lipid peroxidation levels in ferroptosis. This chapter aims to provide comprehensive experimental protocols for detecting lipid peroxidation levels indicative of ferroptosis using C11-BODIPY staining and subsequent detection via flow cytometry and fluorescence microscopy.

Detection of Ferroptosis in Models of Brain Diseases.

Ferroptosis is a regulated form of non-apoptotic cell death driven by iron-dependent lipid peroxidation. In the past decade, ferroptosis has been reported to be involved in the pathological role in the central nervous system degenerative diseases (e.g., Alzheimer's disease, Huntington's disease, and Parkinson's disease), stroke, traumatic brain injury, and brain tumor. However, how to reliably detect and classify ferroptosis from other cell death in pathological conditions remains a great challenge, especially in primary brain cells and brain tissues. Here, we summarize the methods and protocols (such as real-time PCR, western blotting, immunofluorescence staining, lipid peroxidation assay kits and probe, immunofluorescence staining, GPX activity and glutathione depletion assay kits, iron detection, and TEM) used in the present study to detect and classify ferroptosis in the brain.

Reverse cholesterol transport and lipid peroxidation biomarkers in major depression and bipolar disorder: A systematic review and meta-analysis.

BACKGROUND: Major depression (MDD) and bipolar disorder (BD) are linked to immune activation, increased oxidative stress, and lower antioxidant defenses. OBJECTIVES: To systematically review and meta-analyze all data concerning biomarkers of reverse cholesterol transport (RCT), lipid-associated antioxidants, lipid peroxidation products, and autoimmune responses to oxidatively modified lipid epitopes in MDD and BD. METHODS: Databases including PubMed, Google scholar and SciFinder were searched to identify eligible studies from inception to January 10th, 2023. Guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. RESULTS: The current meta-analysis included 176 studies (60 BD and 116 MDD) and examined 34,051 participants, namely 17,094 with affective disorders and 16,957 healthy controls. Patients with MDD and BD showed a) significantly decreased RCT (mainly lowered high-density lipoprotein cholesterol and paraoxonase 1); b) lowered lipid soluble vitamins (including vitamin A, D, and coenzyme Q10); c) increased lipid peroxidation and aldehyde formation, mainly increased malondialdehyde (MDA), 4-hydroxynonenal, peroxides, and 8-isoprostanes; and d) Immunoglobulin (Ig)G responses to oxidized low-density lipoprotein and IgM responses to MDA. The ratio of all lipid peroxidation biomarkers/all lipid-associated antioxidant defenses was significantly increased in MDD (standardized mean difference or SMD = 0.433; 95% confidence intervals (CI): 0.312; 0.554) and BD (SMD = 0.653; CI: 0.501-0.806). This ratio was significantly greater in BD than MDD (p = 0.027). CONCLUSION: In MDD/BD, lowered RCT, a key antioxidant and anti-inflammatory pathway, may drive increased lipid peroxidation, aldehyde formation, and autoimmune responses to oxidative specific epitopes, which all together cause increased immune-inflammatory responses and neuro-affective toxicity.

Lipofuscin, amyloids, and lipid peroxidation as potential markers of aging in Daphnia.

Accumulation of autofluorescent waste products, amyloids, and products of lipid peroxidation (LPO) are important hallmarks of aging. Until now, these processes have not been documented in Daphnia, a convenient model organism for longevity and senescence studies. We conducted a longitudinal cohort study of autofluorescence and Congo Red (CR) fluorescent staining for amyloids in four clones of D. magna. Additionally, we used a single time point cross-sectional common garden experiment within a single clone in which autofluorescence and BODIPY C11 fluorescence were measured. We observed a robust increase in autofluorescent spots that show diagnostic co-staining by Sudan Black indicating lipofuscin aggregates, particularly in the upper body region. There was also a significant clone-by-age interaction indicating that some genotypes accumulated lipofuscins faster than others. Contrary to predictions, CR fluorescence and lipid peroxidation did not consistently increase with age. CR fluorescence demonstrated a slight non-monotonous relationship with age, achieving the highest values at intermediate ages, possibly due to elimination of physiological heterogeneity in our genetically uniform cohorts. LPO demonstrated a significant ovary status-by-age interaction, decreasing with age when measured in Daphnia with full ovaries (late phase ovarian cycle) and showing no significant trend or slight increase with age when measured during the early phase in the ovarian cycle.

Role of ferroptosis in fibrosis diseases.

Ferroptosis is a pervasive non-apoptotic mode of cell death that is different from autophagy or necrosis. It is mainly caused by an imbalance between the production and degradation of lipid reactive oxygen species in cells. Several metabolic pathways and biochemical processes, such as amino acid and lipid metabolism, iron handling, and mitochondrial respiration, affect and regulate cell sensitivity to peroxidation and ferroptosis. Organ fibrosis, a pathological manifestation of several etiological conditions, leads to chronic tissue injury and is characterized by excessive deposition of extracellular matrix components. Excessive tissue fibrosis can have diverse pathophysiological effects on several organ systems, eventually causing organ dysfunction and failure. The current manuscript provides a review that illustrates the link between ferroptosis and organ fibrosis and to better understand the underlying mechanisms. It provides novel potential therapeutic approaches and targets for fibrosis diseases.

[Ferroptosis and drug-induced liver injury].

Ferroptosis is a type of regulated cell death driven by iron-dependent lipid peroxidation that has received extensive attention in recent years. A growing body of evidence suggests that ferroptosis contributes to the progression of drug-induced liver injury. Therefore, the role and mechanism of ferroptosis in the process of drug-induced liver injury deserve further extensive and in-depth exploration, which will aid in the discovery of novel biomarkers as well as the identification of potential approches of targeting ferroptosis to intervene in drug-induced liver injury.

Vitamin A metabolites inhibit ferroptosis.

Vitamin A (retinol) is a lipid-soluble vitamin that acts as a precursor for several bioactive compounds, such as retinaldehyde (retinal) and isomers of retinoic acid. Retinol and all-trans-retinoic acid (atRA) penetrate the blood-brain barrier and are reported to be neuroprotective in several animal models. We characterised the impact of retinol and its metabolites, all-trans-retinal (atRAL) and atRA, on ferroptosis-a programmed cell death caused by iron-dependent phospholipid peroxidation. Ferroptosis was induced by erastin, buthionine sulfoximine or RSL3 in neuronal and non-neuronal cell lines. We found that retinol, atRAL and atRA inhibited ferroptosis with a potency superior to α-tocopherol, the canonical anti-ferroptotic vitamin. In contrast, we found that antagonism of endogenous retinol with anhydroretinol sensitises ferroptosis induced in neuronal and non-neuronal cell lines. Retinol and its metabolites atRAL and atRA directly interdict lipid radicals in ferroptosis since these compounds displayed radical trapping properties in a cell-free assay. Vitamin A, therefore, complements other anti-ferroptotic vitamins, E and K; metabolites of vitamin A, or agents that alter their levels, may be potential therapeutics for diseases where ferroptosis is implicated.

Ferroptosis: mechanisms and implications for cancer development and therapy response.

As cancer cells develop resistance to apoptosis, non-apoptotic cell death modalities, such as ferroptosis, have emerged as promising strategies to combat therapy-resistant cancers. Cells that develop resistance to conventional therapies or metastatic cancer cells have been shown to have increased sensitivity to ferroptosis. Therefore, targeting the regulatory elements of ferroptosis in cancer could offer novel therapeutic opportunities. In this review, we first provide an overview of the known ferroptosis regulatory networks and discuss recent findings on how they contribute to cancer plasticity. We then expand into the critical role of selenium metabolism in regulating ferroptosis. Finally, we highlight specific cases where induction of ferroptosis could be used to sensitize cancer cells to this form of cell death.