Ferroptosis in Cancers and Leukemia: History
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Subjects: Cell Biology
Contributor:
Hiroki Akiyama
,
Bing Z. Carter
,
Michael Andreeff
,
Jo Ishizawa

Ferroptosis is a mode of cell death regulated by iron-dependent lipid peroxidation. Grow- ing evidence suggests ferroptosis induction as a novel anti-cancer modality that could potentially overcome therapy resistance in cancers. The molecular mechanisms involved in the regulation of ferroptosis are complex and highly dependent on context. Therefore, a comprehensive understanding of its execution and protection machinery in each tumor type is necessary for the implementation of this unique cell death mode to target individual cancers. Since most of the current evidence for ferroptosis regulation mechanisms is based on solid cancer studies, the knowledge of ferroptosis with regard to leukemia is largely lacking. In this review, we summarize the current understanding of ferroptosis-regulating mechanisms with respect to the metabolism of phospholipids and iron as well as major anti-oxidative pathways that protect cells from ferroptosis. We also highlight the diverse impact of p53, a master regulator of cell death and cellular metabolic processes, on the regulation of ferroptosis. Lastly, we discuss recent ferroptosis studies in leukemia and provide a future perspective for the development of promising anti-leukemia therapies implementing ferroptosis induction.

  • ferroptosis
  • leukemia
  • iron
  • phospholipid
  • lipid peroxidation
  • p53

1. Introduction

Regulated cell death (RCD) is essential for ontogenetic development and homeostasis, and its dysregulation can result in various pathological conditions, including cancer [1][2]. Apoptosis is the best-established mode of RCD and was first characterized in 1972 by Kerr et al. in both physiological and pathological contexts [3]. Because most cancer cells depend on the dysregulation of apoptosis pathways for their survival, therapeutic interventions targeting these pathways have been studied extensively [4]. During the past few decades, however, numerous studies have uncovered additional modes of RCD whose morphologic features and mechanisms are distinct from those of apoptosis [1][2][5].
Ferroptosis is one of the non-apoptotic modes of RCD characterized by a dependency on iron and lipid peroxidation. The term “ferroptosis” was first coined in 2012 by Dixon et al. as an iron-dependent form of non-apoptotic cell death induced by the RAS-selective lethal small molecules erastin and (1S,3R)-RSL3 (RSL3) [6]. Mechanistically, erastin blocks the uptake of cystine through system xc− and depletes cellular glutathione (GSH). Two years later, Yang et al. discovered that glutathione peroxidase 4 (GPX4) is a target of RSL3 and an essential regulator of ferroptosis in many cancer cell types [7]. Since then, ferroptosis has drawn extensive attention in a variety of biomedical research fields, including anti-viral or anti-tumor immune responses, ischemic organ injury, as well as cancer (detailed review elsewhere [8]). Ferroptosis has also been demonstrated to play important physiological roles, such as erythroid maturation [9], platelet production [10], aging [11], and immune cell functions [12][13][14]. The number of publications related to ferroptosis has grown exponentially over the last decade [5][15]. In particular, ferroptosis induction could be a novel therapeutic strategy for cancers that are resistant to apoptosis and conventional chemotherapy [16][17][18][19]. However, the regulatory pathways and cell death execution machinery of ferroptosis are not yet fully understood. In fact, recent studies indicate a highly variable and context-dependent nature of ferroptosis regulation in cancers [20][21].
Leukemia is characterized by the excessive proliferation, increased survival, and dysregulated differentiation of immature cells originating from hematopoietic stem and progenitor cells. With dysregulation of apoptosis mechanisms being essential components of leukemia development, progression, and therapy resistance, discovery of the BCL-2 inhibitor venetoclax transformed the therapeutic landscape of acute myeloid leukemia (AML) as well as that of chronic lymphocytic leukemia (CLL) [22][23][24]. Nevertheless, a substantial number of patients exhibit primary or acquired resistance to venetoclax-based therapies indicating cell-intrinsic and/or therapy-induced mechanisms of apoptosis resistance, particularly in AML cells [25]; therefore, alternative therapeutic strategies are urgently needed.

2. Molecular Mechanisms of Ferroptosis Induction

The health and survival of most living organisms depend on the tight regulation of cellular reactive oxygen species (ROS), which are highly reactive byproducts of metabolic processes involving oxygen [26]. Excessive ROS can affect various cellular components, including membrane phospholipids, leading to lipid peroxidation and membrane damage [27]. An accumulation of lipid peroxides overwhelms the cells’ antioxidative defense mechanisms, leading to ferroptosis [28][29].
 

3. Mechanisms of Protection from Ferroptosis

3.1. The System xc−—GSH—GPX4 Axis

Ferroptosis was initially described as a form of cell death that is induced by erastin and RSL3 through the inhibition of cystine uptake via system xc− and GPX4, respectively [6]. Given that cystine is an essential component of GSH, which is a co-factor of GPX4, the system xc−-GSH-GPX4 pathway was first established as the core defense mechanism against ferroptosis.
System xc− is a heterodimeric plasma membrane cystine/glutamate antiporter composed of SLC7A11 (xCT) and SLC3A2 (CD98) [30]. System xc− imports cystine while exporting intracellular glutamate. Imported cystine is reduced to cysteine, which is utilized for GSH biosynthesis. Cystine availability also promotes GPX4 protein synthesis through the activation of the mammalian target of rapamycin complex 1 (mTORC1) [31]. A minor portion of intracellular cysteine pool can also be synthesized de novo from methionine through the transsulfuration pathway [32]. The activation of this pathway through cystathionine β-synthase (CBS) [33] or S-adenosyl homocysteine hydrolase (SAHH) [34] confers resistance to ferroptosis. GSH is synthesized from cysteine via sequential enzymatic reactions involving the rate-limiting γ-glutamylcysteine synthetase (γ-GCS) and glutathione synthetase (GSS) [35]. The inactivation of system xc− (e.g., by erastin) or the depletion of cystine from culture media has been reported to induce ferroptosis in a wide variety of cancer models [36][37][38]. Recently, Pardieu et al. studied the anti-leukemia effects of cystine depletion in AML and found that ferroptosis comprised only a part of the mechanisms of cell death induced [39]. The depletion of GSH also induces a mixture of cell death modes including ferroptosis [40][41]. Intriguingly, one recent study indicated that γ-GCS has a non-canonical, GSH-independent role in protecting cells from ferroptosis through the synthesis of γ-glutamyl peptides and the inhibition of glutamate stress [42]. In fact, glutamate metabolism is also known as a regulator of ferroptosis; the inhibition of SLC1A5-mediated glutamine uptake, the mitochondrial glutaminase (GLS2)–mediated synthesis of glutamate from glutamine, and the glutamic-oxaloacetic transaminase 1 (GOT1)–mediated synthesis of α-ketoglutarate from glutamate, can all suppress ferroptosis [43].
GPX4 is the only mammalian enzyme that catalyzes the reduction of lipid peroxides into nontoxic alcohols [44]. Since the discovery that RSL3 targets GPX4 to induce ferroptosis [7], a number of studies have established the roles of GPX4 as a central repressor of ferroptosis [31][45][46][47]. Importantly, therapy-resistant or -persistent solid cancer cells with a mesenchymal gene signature exhibit vulnerability to GPX4 inhibition, which suggests that targeting GPX4 has therapeutic potential in certain intractable phases or types of cancers [16][17]. Because GPX4 is a selenoprotein, its synthesis and activity are regulated by cellular selenium availability [48]. Therefore, the incorporation of selenium within GPX4 is also important for protecting cells from ferroptosis [49][50]. Mammalian GPX4 consists of three isoforms with distinct subcellular localizations: short, long, and nuclear isoforms of GPX4 (from here, we describe them simply as short, long, and nuclear GPX4). Whereas long GPX4 contains a mitochondria-targeting sequence and is transported into the mitochondrial matrix, short GPX4 mainly resides in the cytosol [51]. Of note, a portion of short GPX4 is translocated into the mitochondria in a mitochondria-targeted sequence–independent manner [52]. Only short GPX4 was initially believed to be important for cell protection against ferroptosis, mainly because short GPX4, but not the other GPX4 isoforms, rescues the lethal phenotype of GPX4 knockout in mice [52][53][54]. However, recent studies have demonstrated that long GPX4 also plays an important role in ferroptosis protection in doxorubicin-induced cardiomyopathy [55][56][57] and in cancer models under certain conditions, as described in the following Section 3.3 [58][59][60].

3.2. The Ferroptosis Suppressor Protein 1-Coenzyme Q Axis

In 2019, two groups independently reported a GPX4-independent mechanism of ferroptosis protection that involves ferroptosis suppressor protein 1 (FSP1, formerly known as apoptosis inducing factor mitochondria associated 2 [AIFM2]) [61][62]. FSP1 localizes on the plasma membrane and reduces ubiquinone, or coenzyme Q (CoQ), to ubiquinol (CoQH2). In fact, CoQ/CoQH2 works not only as an electron carrier in the mitochondrial electron transport chain complex but also as a major endogenous lipophilic radical-trapping antioxidant that protects cells from lipid peroxidation [63]. In this reaction, CoQH2 reduces lipid peroxides and is oxidized to CoQ, which is then recycled back to CoQH2 by FSP1 using NADPH. Indeed, NADPH was identified as a predictive biomarker of ferroptosis sensitivity in cancer cell lines [64], and its depletion by the phosphatase guanosine-3′,5′-bis(diphosphate) 3′-pyrophosphohydrolase (MESH1) facilitates ferroptosis [65]. Using Kelch-like ECH-associated protein 1 (KEAP1)–mutant lung cancer models, Koppula et al. demonstrated that the FSP1-CoQ axis is regulated by the KEAP1–nuclear factor erythroid 2–related factor 2 (NRF2) pathway [66]. The mouse double minute 2 (MDM2)–murine double minute X (MDMX) complex also regulates FSP1 through peroxisome proliferator-activated receptor α (PPARα) in a p53-independent manner to promote ferroptosis [67]. Recently, Mishima et al. discovered that vitamin K is another substrate of FSP1 that protects cells from ferroptosis [68], and they demonstrated that the reduced form of vitamin K is a potent radical-trapping antioxidant that inhibits lipid peroxidation.

3.3. The Dihydroorate Dehydrogenase/Glycerol-3-Phosphate Dehydrogenase 2–Mitochondrial CoQ Axis

Two recent studies uncovered mitochondria-specific ferroptosis defense mechanisms that are independent of cytosolic anti-ferroptosis pathways. In one study, Mao et al. found that dihydroorate dehydrogenase (DHODH), an enzyme required for pyrimidine synthesis, reduces CoQ to CoQH2 in the mitochondrial inner membrane to protect cells from ferroptosis [59]. The same group also found that glycerol-3-phosphate dehydrogenase 2 (GPD2) is another enzyme that couples glycerol-3-phosphate oxidation with mitochondrial CoQ reduction to suppress ferroptosis [60]. Importantly, these mitochondria-specific machineries cooperate with mitochondria-localized long GPX4, but not short GPX4, to suppress mitochondrial membrane lipid peroxidation to protect cells from GPX4 inhibition–induced ferroptosis. These studies suggest the importance of subcellular compartmentalization in ferroptosis defense mechanisms [69].

3.4. The GTP Cyclohydrolase 1–Tetrahydrobiopterin–Dihydrofolate Reductase Axis

GTP cyclohydrolase 1 (GCH1) is another GPX4-independent regulator of ferroptosis [20][70]. It protects cells from lipid peroxidation through the production of tetrahydrobiopterin (BH4) and dihydrobiopterin (BH2). BH4 and BH2 are endogenous radical-trapping antioxidants and are generated by dihydrofolate reductase (DHFR). BH4 is also involved in the synthesis of reduced CoQH2 and the depletion of PUFA-containing phospholipids.

4. Regulation of Ferroptosis by p53

The “guardian of the genome”, p53, is a well-established tumor suppressor. Owing to deletion and/or loss-of-function mutations, p53 has deficient function in approximately half of human cancers [71]. Many other cancers overexpress MDM2 or MDMX, which results in degradation of p53 [72]. Patients who have AML with TP53 mutations—an AML subtype that is one of the most challenging to treat—have low treatment response rates and poor survival [73]. In addition to its canonical roles of inducing cell cycle arrest, senescence, apoptosis, and DNA damage repair, p53 regulates multiple nodes of cellular metabolism, including iron, lipid, and redox metabolism, and thus plays important roles in the regulation of ferroptosis.
In 2015, Jian et al. reported that functional p53 directly suppresses SLC7A11 to induce ferroptosis and inhibit tumor development [74]. They demonstrated that acetylation-deficient TP533KR mutants can efficiently induce ferroptosis while losing their ability to upregulate canonical p53 target genes (e.g., CDKN1A/p21, PUMA). Another study showed that the mutation of all four acetylation sites in TP53 (i.e., TP534KR) abolishes the gene’s effect against SLC7A11 and thus eliminates its tumor-suppressive function. These studies indicate that p53, through its regulation of senescence, apoptosis, and ferroptosis, has distinct functions as a tumor suppressor. Another study also demonstrates that mutant p53 (e.g., TP53R175H) retains the ability to repress the expression of SLC7A11 by inhibiting NRF2-mediated transcription programs [75]. Several metabolism-associated genes, including ALOX12 [76], the spermidine/spermine N1-acetyltransferase 1 gene SAT1 [77], and the ferredoxin reductase gene FDXR [78], are important for the regulation of p53-induced ferroptosis. Another p53 target, GLS2, promotes ferroptosis through the regulation of glutaminolysis; however, further investigation is needed to determine the specific role of GLS2 in p53-mediated ferroptosis [43][79].
Intriguingly, p53 can also suppress ferroptosis under certain conditions. Tarangelo et al. reported that, in contrast to the aforementioned SLC7A11 suppression and ferroptosis induction mediated by p53, the stabilization of wild-type p53 by MDM2-p53 interaction, by inducing p21 and de novo GSH synthesis, delays ferroptosis induced by system xc− inhibition or cysteine deprivation [80]. Another direct target of p53 is calcium-independent phospholipase A2 group VI (iPLA2β), which detoxifies membrane lipid peroxidation to protect cells from ferroptosis [81]. Kuganesan et al., dissecting the roles of p53 and downstream p21, CDKs, RB, and E2F in ferroptosis modulation [82], speculated that multiple pro-ferroptosis and anti-ferroptosis signals may emanate from the individual nodes of p53 pathways, leading to context-dependent outcomes against ferroptosis stimuli and tumor progression.
Taken together, the role of p53 in ferroptosis regulation is highly complex and context dependent. Extensive reviews on this topic are available elsewhere [83][84][85].

5. Ferroptosis in Leukemia

5.1. Dysregulation of Iron Homeostasis in Leukemia

Leukemia patients are characterized by systemic iron overload due to multiple factors. The most common reason is repetitive red blood cell transfusions that lead to massive iron intake over the courses of disease [86]. Ineffective erythropoiesis and a high turnover of immature erythrocytes can also lead to iron overload, especially in AML associated with myelodysplasia. Mechanistically, ineffective erythropoiesis suppresses hepcidin leading to enhanced iron uptake [87]. Hematopoietic stem cell transplantation can also disturb iron homeostasis by suppressing erythropoiesis and by erythroid cell lysis, which can affect patients’ survival [88][89]. Lopes et al. recently reported on iron redistribution in AML cells [90]. They found that AML patients have increased transferrin saturation (TSAT) and high hepcidin irrespective of transfusion history, indicating increased levels of circulating iron. Furthermore, using electron microscopy combined with energy-dispersive X-ray spectroscopy for elemental analysis and flow cytometry for LIP quantification, they found increased intracellular iron levels in AML cells. Compared to healthy bone marrow cells, AML cells show increased expression of HO-1 and ferritin light chain 1 (FTL1), indicative of intracellular iron accumulation. The expression level of the iron importer TFR1 in leukemia cells is similar to that in healthy bone marrow cells but lower than that in erythroblasts, which suggests that leukemia cells have a relatively low iron demand [90][91].
The correlation of dysregulated iron metabolism and patient outcome in leukemia, however, remain unclear. The low expression level of the iron exporter FPN1 in AML cells is associated with chemosensitivity and better patient outcome [92]. In another study, Trujillo-Alonso et al. showed that the expression levels of FPN1 in primary AML blasts and leukemia stem cells are lower than that in healthy bone marrow CD34+ hematopoietic stem progenitor cells [93]. They demonstrated that low FPN1 expression leads to increased intracellular iron and oxidative stress, which sensitized cells to the iron oxide nanoparticle ferumoxytol. Together, these data suggest that leukemia cells have impaired iron flux and intracellular iron accumulation, which may render them vulnerable to ferroptosis induction.

5.2. Ferroptosis-Related Gene Signatures in Leukemia

Since ferroptosis was first identified as a distinct type of cell death, numerous studies have identified molecular regulators of this complicated cell death process. This extensive knowledge is organized in FerrDb, a publicly available database of ferroptosis-related genes and their associated diseases [94][95]. High-throughput gene testing with microarrays and, more recently, RNA sequencing, have enabled researchers to capture gene expression patterns as gene signatures that can be used to identify multiple clusters among patients with heterogeneous cancers based on their genetic backgrounds and to predict prognosis [96].
On the basis of these patient datasets, including those in the Cancer Genome Atlas (TCGA), multiple groups have defined ferroptosis-related genes (FRGs) and have correlated their expression with patient survival to develop FRG scoring models that can predict prognosis and ex vivo drug sensitivities in association with their clinical characteristics in AML [97][98][99][100][101][102][103][104], acute lymphoblastic leukemia (ALL) [105], and CLL [106][107]. Interestingly, many FRG signatures are associated with immune-related pathways and immune cell infiltration predicted by CIBERSORTx gene-expression profiling analyses, which suggests that ferroptosis has relevance in anti-tumor immune responses and potentially in immunotherapy in leukemia. In addition to FRGs’ expression levels, their methylation status [108] and copy number variations [109] have also been reported to have prognostic significance. One group studying the correlation of long non-coding RNAs (lncRNAs) and FRGs identified ferroptosis-related lncRNA signatures that predict the prognosis of AML [110].
Although multiple FRG signatures share some genes (e.g., GPX4, AIFM2), these models are based on different datasets and statistical methods, which has resulted in distinct scoring systems with individual clinical relevance. Further validations in independent datasets are warranted to ensure the robustness of a model to be applied in clinical practice, including in terms of its prognosis prediction and treatment optimization. In addition, basic in vitro and in vivo experiments are needed to verify the expression level and determine the biological role(s) of each FRG. Of note, ferroptosis-related prognostic gene signatures developed from the pediatric AML dataset in the National Cancer Institute’s Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Initiative could not be validated in an adult AML dataset from TCGA [111], likely because of the two cohorts’ distinct genetic landscapes and clinical characteristics.

5.3. Ferroptosis Induction as a Therapeutic Strategy in Leukemia

Ferroptosis induction has been demonstrated to exert anti-tumor effects in various leukemia models. Most of the evidence is based on in vitro experiments using cell lines or patient-derived primary cells, but some of the studies include in vivo models. Not only classic ferroptosis inducers (e.g., system xc−/GSH/GPX4 inhibitors) but also natural compound derivatives and other small molecules are shown to induce ferroptosis as a mechanism of their anti-leukemia activities.

5.3.1. Inhibition of System xc-—GSH—GPX4 Axis in Leukemia

The first study of ferroptosis in AML was reported in 2015 by Yu et al., who demonstrated that the system xc- inhibitor erastin induces ferroptosis in HL-60 cells in vitro [184]. The cell death was a mixture of ferroptosis and necroptosis, as it was blocked not only by ferrostatin-1 and deferoxamine but also by necrostatin-1 and the knockdown of receptor-interacting protein 3 (RIP3). They also demonstrated the association of autophagy and p38 signaling, the inhibition of which attenuated the anti-leukemia effects of erastin. Later, erastin-induced ferroptosis in HL-60 cells was shown to depend on the cytoplasmic translocation of high mobility group box 1 (HMGB1) from the nucleus, the knockdown of which attenuated ferroptosis in vivo [185]. Recently, Pardieu et al. reported that the xCT gene SLC7A11 is a putative therapeutic vulnerability, especially in NPM1-mutated AML, and a poor prognostic factor [113]. They demonstrated that the system xc- inhibitor sulfasalazine suppressed GSH and induced oxidative stress–dependent cell death partly through ferroptosis, as indicated by its partial rescue by ferrostatin-1. The combination of sulfasalazine with daunorubicin and cytarabine was found to synergistically exert anti-leukemia effects in a patient-derived xenograft model as well as in primary AML cells. A clinical trial of sulfasalazine in combination with intensive chemotherapy in AML patients is being initiated (NCT05580861). K562 chronic myeloid leukemia cells were tested for cysteine depletion-induced ferroptosis [188]. The authors demonstrated that the concomitant inhibition of thioredoxin reductase 1 (TXNRD1) by auranofin leads to ferroptosis in these cells. Interestingly, K562 cells with imatinib resistance (K562/G0 cells) showed higher sensitivity to ferroptosis induced by cysteine depletion.

5.3.2. Ferroptosis Induction by Clinically Available Anti-Leukemia Agents

Hypomethylating agents are used as a standard of care for elderly patients with AML and for patients with myelodysplastic syndromes (MDS) [208]. One hypomethylating agent, decitabine, has been shown to induce ferroptosis and necroptosis in MDS-derived primary cells as well as cell lines [189]. It downregulates GSH and GPX4 while inducing ROS and cell death, which can be blocked by ferrostatin-1, necrostatin-1, and z-VAD-FMK. These data indicate that ferroptosis is at least partially involved in the effect of decitabine.

Wang et al. investigated the anti-leukemia effects observed for the combination of granulocyte-colony stimulating factor (G-CSF) and thrombopoietin (TPO) with low-dose chemotherapy investigated in a phase 2 trial in elderly AML patients [209]. They demonstrate that TPO induces ferroptosis through the suppression of E1A binding protein P300 (EP300)–mediated GPX4 transcription, whereas G-CSF induces pyroptosis through neutrophil elastase, which activates gasdermin D (GSDMD) in AML cells [190].

In 2020, Birsen et al. reported that, independent of its postulated effects against mutant TP53, APR-246 induces ferroptosis in AML cells during the early phases of drug exposure [191]. Ferroptosis induction by APR-246 was later confirmed in esophageal cancer cell lines, which showed an increase in GSH turnover and the suppression of mitochondrial iron-sulfur cluster biosynthesis through NFS1 [210].

Imetelstat is a first-in-class telomerase inhibitor currently under a phase 2 clinical trial against AML (NCT05583552), in addition to phase 3 clinical trial against myelodysplastic syndromes and myelofibrosis. A functional genetic screen combined with lipidomics revealed that imetelstat promotes PUFA-containing phospholipid synthesis in ACSL4– and FADS2–dependent manner, leading to AML cell ferroptosis both in vitro and in vivo [192]. However, it has not yet been shown whether the induced ferroptosis is telomerase-dependent or drug-specific off-target effects.

The tyrosine kinase inhibitor Neratinib was approved by the U.S. Food and Drug Administration in 2017 for the treatment of breast cancer, and a phase 1/2 clinical trial of this drug in pediatric patients with relapsed or refractory cancer including leukemia is ongoing (NCT02932280). Recently, neratinib has been shown to induce autophagy-dependent ferroptosis as well as G0/G1 arrest and apoptosis in HL-60 cells [193].

5.3.3. Ferroptosis Induction by Natural Compounds and Their Derivatives

Many natural compounds have been studied for their ability to induce ferroptosis in cancer cells [211]. Dihydroartemisinin is a derivative of Artemisia annua, a plant native to China, and has anti-tumor effects in many types of cancers. This compound has effects against HL-60 cells in vitro and in vivo through the inhibition of mitochondrial oxidative phosphorylation and the activation of AMPK to induce ferritinophagy and ferroptosis [194]. Typhaneoside, a flavonoid extracted from Pollen typhae, has also been reported to induce apoptosis and ferroptosis associated with ferritinophagy in AML cells [195]. Hydnocarpin D is another flavonoid demonstrated to induce apoptosis and ferroptosis through autophagy in ALL cells [196]. Perillaldehyde, the main component of Ammodaucus leucotrichus, downregulates GSH and GPX4 to induce ferroptosis in HL-60 cells and primary AML cells [197]. Glycyrrhetinic acid is a bioactive compound of licorice, and its nanoparticles have been demonstrated to induce ferroptosis in AML cells through GPX4 downregulation [198]. These nanoparticles have synergistic anti-leukemia effects with ferumoxytol, an iron oxide nanoparticle, and programmed cell death ligand 1 (PD-L1) antibody treatment. The isothiocyanate sulforaphane (SFN) is derived from cruciferous vegetables and is known to exert anti-cancer activities. Greco et al. reported that low-dose SFN induces apoptosis whereas high-dose SFN induces ferroptosis in AML cell lines [199]. Interestingly, SFN activates the apoptosis pathway when ferroptosis is impaired, indicating that these two cell death modes could be convertible. Honokiol, a derivative of the magnolia tree, induces cell death in AML cell lines; this cell death was triggered by the upregulation of HO-1 and associated with lipid peroxidation and the alteration of ferroptosis pathway genes [200]. 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a retinoid derivative synthesized from all-trans retinoic acid (ATRA), has been shown to activate NCOA4-dependent ferritinophagy and induce ferroptosis in AML in vitro and in vivo [201]. Poricoic acid A, the component of the mushroom Poria cocos, exerts anti-ALL effects in vitro and in vivo through mitochondrial dysfunction and activation of AMPK-mTOR autophagy pathway, leading to apoptosis and ferroptosis in T-ALL cells [202].

5.3.4. Other Potential Therapeutic Strategies Inducing Ferroptosis in Leukemia

ALDH3a2, an enzyme that oxidizes long-chain aliphatic aldehydes, which are byproducts of lipid peroxidation, protects AML cells from oxidative stress. The inhibition of ALDH3a2 induces ferroptosis and exerts synergistic anti-leukemia effects with GPX4 inhibition or standard chemotherapy with cytarabine plus daunorubicin in vivo [96]. In addition, ALDH3a2 is selectively essential in leukemia progenitor cells but not in their normal counterparts, possibly owing to increased oxidative stress in leukemia cells.

Gold nanoparticles have anti-leukemia effects in part through ferroptosis induction. For example, GNR-CSP12 (gold nanorods loaded with chitosan and a 12-mer peptide) can induce ferroptosis through the suppression of global m6A RNA methylation and its combinatorial effects with tyrosine kinase inhibitors or PD-L1 checkpoint inhibitors [203].

Non-coding RNAs have also been reported to be involved in ferroptosis regulation in AML cells. A nuclear long non-coding RNA (lncRNA), LINC00618, is downregulated in AML, and its induction by vincristine treatment activates ferroptosis and apoptosis through SLC7A11 downregulation and BAX upregulation as well as caspase-3 cleavage [204]. The circular RNA circKDM4C, which is also downregulated in AML, sequesters the microRNA hsa-let-7b-5p and upregulates its downstream target, p53 [205]. The induction of circKDM4C causes AML cells to undergo ferroptosis, possibly through the downregulation of GPX4 and FTH1.

 

  1. Conclusions and Future Perspectives

Recent discoveries of various non-apoptotic RCD modes, including ferroptosis, have expanded the potential modalities to induce death in cancer cells, especially in cancers resistant to conventional therapies targeting apoptosis mechanisms. A comprehensive understanding of the complex regulatory mechanisms of RCD and its involvement in cancer pathophysiology is necessary to develop RCD modes different from apoptosis into advanced cancer therapies.

While more than 10 years of extensive research has provided us with a large body of knowledge about ferroptosis, one needs to be cautious as most of our current mechanistic insights are based on in vitro models, whose environments differ from those in vivo. Components of the in vivo environment that likely affect ferroptosis regulation include oxygen; trace metals, including iron and selenium; and various metabolites such as amino acids and fatty acids. In addition, interactions with the tumor immune microenvironment (i.e., macrophages and immune cells) and even between cancer cells have been shown to affect cell vulnerability to ferroptosis, a complexity that is difficult to recapitulate in culture models. In fact, mesenchymal stem cells (MSCs) protect leukemia cells from oxidative stress through upregulation of GSH [212,213], while its significance in ferroptosis protection remains to be elucidated. Therefore, the in vitro findings must be validated in vivo to obtain a precise understanding of the mechanisms regulating ferroptosis, for which further development of specific and stable in vivo drugs to induce ferroptosis is of urgent need. The lack of definitive markers of ferroptosis is an obstacle in studying ferroptosis in vivo and in clinical settings in humans. Hence, direct evidence of ferroptosis in cancer patients treated with anti-cancer agents including ferroptosis inducers is lacking so far [214].

Since leukemia is characterized by increased oxidative stress and iron overload, one can speculate that leukemia cells are vulnerable to ferroptosis, suggesting a therapeutic potential. However, studies focusing on ferroptosis as a therapeutic modality for leukemia are limited, as discussed here. Given the physiological roles of ferroptosis, the therapeutic windows of ferroptosis induction should be carefully determined. A recent study demonstrated the potential vulnerability of hematopoietic stem cells to ferroptosis [215], warranting precise monitoring of normal hematopoiesis upon anti-cancer treatments involving ferroptosis. Taken together, implementing the concept of ferroptosis into leukemia therapeutics requires fine-tuning ferroptosis induction in normal versus malignant cells, which should be tested and established through in vivo studies and ultimately clinical trials.

In addition to understanding the underlying molecular mechanisms of ferroptosis, some of which may be specific to leukemia cells, identifying potential biomarkers that predict sensitivity or resistance to ferroptotic stimuli is critical for the development of this unique cell death mode as anti-leukemia therapy. Advancements in single-cell analysis technologies will help in the identification of potential vulnerabilities of leukemia stem/progenitor cells with specific genetic or molecular phenotypes that can be targeted for ferroptosis induction. Pursuing synthetic lethal interactions would be one promising strategy to efficiently target those populations while minimizing potential toxicity to normal cells [216]. Lastly, recent studies have revealed the interconnectivity and plasticity of different RCD pathways including ferroptosis that could compensate each other upon cell death stimuli (detailed review elsewhere [217]). Understanding the interactions as well as the molecular mechanisms of individual RCD pathways would facilitate the development of combination therapies to overcome resistance to various RCD mechanisms.

This entry is adapted from the peer-reviewed paper 10.3390/cells12081128

References

  1. Galluzzi, L.; Vitale, I.; Aaronson, S.A.; Abrams, J.M.; Adam, D.; Agostinis, P.; Alnemri, E.S.; Altucci, L.; Amelio, I.; Andrews, D.W.; et al. Molecular mechanisms of cell death: Recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018, 25, 486–541.
  2. Tang, D.; Kang, R.; Berghe, T.V.; Vandenabeele, P.; Kroemer, G. The molecular machinery of regulated cell death. Cell Res. 2019, 29, 347–364.
  3. Kerr, J.F.; Wyllie, A.H.; Currie, A.R. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 1972, 26, 239–257.
  4. Carneiro, B.A.; El-Deiry, W.S. Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol. 2020, 17, 395–417.
  5. Leak, L.; Dixon, S.J. Surveying the landscape of emerging and understudied cell death mechanisms. Biochim. Biophys. Acta Mol. Cell Res. 2023, 1870, 119432.
  6. Dixon, S.J.; Lemberg, K.M.; Lamprecht, M.R.; Skouta, R.; Zaitsev, E.M.; Gleason, C.E.; Patel, D.N.; Bauer, A.J.; Cantley, A.M.; Yang, W.S.; et al. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012, 149, 1060–1072.
  7. Yang, W.S.; SriRamaratnam, R.; Welsch, M.E.; Shimada, K.; Skouta, R.; Viswanathan, V.S.; Cheah, J.H.; Clemons, P.A.; Shamji, A.F.; Clish, C.B.; et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014, 156, 317–331.
  8. Stockwell, B.R. Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 2022, 185, 2401–2421.
  9. Zheng, H.; Jiang, L.; Tsuduki, T.; Conrad, M.; Toyokuni, S. Embryonal erythropoiesis and aging exploit ferroptosis. Redox Biol. 2021, 48, 102175.
  10. Song, B.; Miao, W.; Cui, Q.; Shi, B.; Zhang, J.; Qiu, H.; Zhang, L.; Han, Y. Inhibition of ferroptosis promotes megakaryocyte differentiation and platelet production. J. Cell Mol. Med. 2022, 26, 3582–3585.
  11. Mazhar, M.; Din, A.U.; Ali, H.; Yang, G.; Ren, W.; Wang, L.; Fan, X.; Yang, S. Implication of ferroptosis in aging. Cell Death Discov. 2021, 7, 149.
  12. Ma, X.; Xiao, L.; Liu, L.; Ye, L.; Su, P.; Bi, E.; Wang, Q.; Yang, M.; Qian, J.; Yi, Q. CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability. Cell Metab. 2021, 33, 1001–1012.e5.
  13. Xu, S.; Chaudhary, O.; Rodriguez-Morales, P.; Sun, X.; Chen, D.; Zappasodi, R.; Xu, Z.; Pinto, A.F.M.; Williams, A.; Schulze, I.; et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8+ T cells in tumors. Immunity 2021, 54, 1561–1577.e7.
  14. Yao, Y.; Chen, Z.; Zhang, H.; Chen, C.; Zeng, M.; Yunis, J.; Wei, Y.; Wan, Y.; Wang, N.; Zhou, M.; et al. Selenium-GPX4 axis protects follicular helper T cells from ferroptosis. Nat. Immunol. 2021, 22, 1127–1139.
  15. Xiong, J.; Qi, W.; Liu, J.; Zhang, Z.; Wang, Z.; Bao, J.; Wu, C.; Liang, F. Research Progress of Ferroptosis: A Bibliometrics and Visual Analysis Study. J. Healthc. Eng. 2021, 2021, 2178281.
  16. Hangauer, M.J.; Viswanathan, V.S.; Ryan, M.J.; Bole, D.; Eaton, J.K.; Matov, A.; Galeas, J.; Dhruv, H.D.; Berens, M.E.; Schreiber, S.L.; et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 2017, 551, 247–250.
  17. Viswanathan, V.S.; Ryan, M.J.; Dhruv, H.D.; Gill, S.; Eichhoff, O.M.; Seashore-Ludlow, B.; Kaffenberger, S.D.; Eaton, J.K.; Shimada, K.; Aguirre, A.J.; et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 2017, 547, 453–457.
  18. Liu, X.; Zhang, Y.; Wu, X.; Xu, F.; Ma, H.; Wu, M.; Xia, Y. Targeting Ferroptosis Pathway to Combat Therapy Resistance and Metastasis of Cancer. Front. Pharm. 2022, 13, 909821.
  19. Lei, G.; Zhuang, L.; Gan, B. Targeting ferroptosis as a vulnerability in cancer. Nat. Rev. Cancer 2022, 22, 381–396.
  20. Soula, M.; Weber, R.A.; Zilka, O.; Alwaseem, H.; La, K.; Yen, F.; Molina, H.; Garcia-Bermudez, J.; Pratt, D.A.; Birsoy, K. Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat. Chem. Biol. 2020, 16, 1351–1360.
  21. Magtanong, L.; Mueller, G.D.; Williams, K.J.; Billmann, M.; Chan, K.; Armenta, D.A.; Pope, L.E.; Moffat, J.; Boone, C.; Myers, C.L.; et al. Context-dependent regulation of ferroptosis sensitivity. Cell Chem. Biol. 2022, 29, 1409–1418.e6.
  22. Ball, S.; Borthakur, G. Apoptosis targeted therapies in acute myeloid leukemia: An update. Expert Rev. Hematol. 2020, 13, 1373–1386.
  23. Maiti, A.; Carter, B.Z.; Andreeff, M.; Konopleva, M.Y. Beyond BCL-2 Inhibition in Acute Myloid Leukemia: Other Approaches to Leverage the Apoptotic Pathway. Clin. Lymphoma Myeloma Leuk. 2022, 22, 652–658.
  24. Lasica, M.; Anderson, M.A. Review of Venetoclax in CLL, AML and Multiple Myeloma. J. Pers. Med. 2021, 11, 463.
  25. Ong, F.; Kim, K.; Konopleva, M.Y. Venetoclax resistance: Mechanistic insights and future strategies. Cancer Drug Resist. 2022, 5, 380–400.
  26. Sies, H.; Jones, D.P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat. Rev. Mol. Cell Biol. 2020, 21, 363–383.
  27. Gaschler, M.M.; Stockwell, B.R. Lipid peroxidation in cell death. Biochem. Biophys. Res. Commun. 2017, 482, 419–425.
  28. Stockwell, B.R.; Jiang, X. The Chemistry and Biology of Ferroptosis. Cell Chem. Biol. 2020, 27, 365–375.
  29. Jiang, X.; Stockwell, B.R.; Conrad, M. Ferroptosis: Mechanisms, biology and role in disease. Nat. Rev. Mol. Cell Biol. 2021, 22, 266–282.
  30. Lo, M.; Wang, Y.Z.; Gout, P.W. The xc− cystine/glutamate antiporter: A potential target for therapy of cancer and other diseases. J. Cell Physiol. 2008, 215, 593–602.
  31. Zhang, Y.; Swanda, R.V.; Nie, L.; Liu, X.; Wang, C.; Lee, H.; Lei, G.; Mao, C.; Koppula, P.; Cheng, W.; et al. mTORC1 couples cyst(e)ine availability with GPX4 protein synthesis and ferroptosis regulation. Nat. Commun. 2021, 12, 1589.
  32. Zhang, H.F.; Klein Geltink, R.I.; Parker, S.J.; Sorensen, P.H. Transsulfuration, minor player or crucial for cysteine homeostasis in cancer. Trends Cell. Biol. 2022, 32, 800–814.
  33. Liu, N.; Lin, X.; Huang, C. Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance. Br. J. Cancer 2020, 122, 279–292.
  34. Cao, J.; Chen, X.; Jiang, L.; Lu, B.; Yuan, M.; Zhu, D.; Zhu, H.; He, Q.; Yang, B.; Ying, M. DJ-1 suppresses ferroptosis through preserving the activity of S-adenosyl homocysteine hydrolase. Nat. Commun. 2020, 11, 1251.
  35. Lu, S.C. Glutathione synthesis. Biochim. Biophys. Acta 2013, 1830, 3143–3153.
  36. Koppula, P.; Zhuang, L.; Gan, B. Cystine transporter SLC7A11/xCT in cancer: Ferroptosis, nutrient dependency, and cancer therapy. Protein Cell 2021, 12, 599–620.
  37. Zhang, Y.; Tan, H.; Daniels, J.D.; Zandkarimi, F.; Liu, H.; Brown, L.M.; Uchida, K.; O’Connor, O.A.; Stockwell, B.R. Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model. Cell Chem. Biol. 2019, 26, 623–633.e9.
  38. Badgley, M.A.; Kremer, D.M.; Maurer, H.C.; DelGiorno, K.E.; Lee, H.J.; Purohit, V.; Sagalovskiy, I.R.; Ma, A.; Kapilian, J.; Firl, C.E.M.; et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 2020, 368, 85–89.
  39. Pardieu, B.; Pasanisi, J.; Ling, F.; Dal Bello, R.; Penneroux, J.; Su, A.; Joudinaud, R.; Chat, L.; Wu, H.C.; Duchmann, M.; et al. Cystine uptake inhibition potentiates front-line therapies in acute myeloid leukemia. Leukemia 2022, 36, 1585–1595.
  40. Cao, J.Y.; Dixon, S.J. Mechanisms of ferroptosis. Cell Mol. Life Sci. 2016, 73, 2195–2209.
  41. Sun, Y.; Zheng, Y.; Wang, C.; Liu, Y. Glutathione depletion induces ferroptosis, autophagy, and premature cell senescence in retinal pigment epithelial cells. Cell Death Dis. 2018, 9, 753.
  42. Kang, Y.P.; Mockabee-Macias, A.; Jiang, C.; Falzone, A.; Prieto-Farigua, N.; Stone, E.; Harris, I.S.; DeNicola, G.M. Non-canonical Glutamate-Cysteine Ligase Activity Protects against Ferroptosis. Cell Metab. 2021, 33, 174–189.e7.
  43. Gao, M.; Monian, P.; Quadri, N.; Ramasamy, R.; Jiang, X. Glutaminolysis and Transferrin Regulate Ferroptosis. Mol. Cell 2015, 59, 298–308.
  44. Ursini, F.; Maiorino, M.; Gregolin, C. The selenoenzyme phospholipid hydroperoxide glutathione peroxidase. Biochim. Biophys. Acta 1985, 839, 62–70.
  45. Shimada, K.; Skouta, R.; Kaplan, A.; Yang, W.S.; Hayano, M.; Dixon, S.J.; Brown, L.M.; Valenzuela, C.A.; Wolpaw, A.J.; Stockwell, B.R. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat. Chem. Biol. 2016, 12, 497–503.
  46. Zou, Y.; Palte, M.J.; Deik, A.A.; Li, H.; Eaton, J.K.; Wang, W.; Tseng, Y.Y.; Deasy, R.; Kost-Alimova, M.; Dancik, V.; et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat. Commun. 2019, 10, 1617.
  47. Eaton, J.K.; Furst, L.; Ruberto, R.A.; Moosmayer, D.; Hilpmann, A.; Ryan, M.J.; Zimmermann, K.; Cai, L.L.; Niehues, M.; Badock, V.; et al. Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles. Nat. Chem. Biol. 2020, 16, 497–506.
  48. Conrad, M.; Proneth, B. Selenium: Tracing Another Essential Element of Ferroptotic Cell Death. Cell Chem. Biol. 2020, 27, 409–419.
  49. Ingold, I.; Berndt, C.; Schmitt, S.; Doll, S.; Poschmann, G.; Buday, K.; Roveri, A.; Peng, X.; Porto Freitas, F.; Seibt, T.; et al. Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis. Cell 2018, 172, 409–422.e21.
  50. Alim, I.; Caulfield, J.T.; Chen, Y.; Swarup, V.; Geschwind, D.H.; Ivanova, E.; Seravalli, J.; Ai, Y.; Sansing, L.H.; Ste Marie, E.J.; et al. Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke. Cell 2019, 177, 1262–1279.e25.
  51. Savaskan, N.E.; Ufer, C.; Kuhn, H.; Borchert, A. Molecular biology of glutathione peroxidase 4: From genomic structure to developmental expression and neural function. Biol. Chem. 2007, 388, 1007–1017.
  52. Liang, H.; Yoo, S.E.; Na, R.; Walter, C.A.; Richardson, A.; Ran, Q. Short form glutathione peroxidase 4 is the essential isoform required for survival and somatic mitochondrial functions. J. Biol. Chem. 2009, 284, 30836–30844.
  53. Schneider, M.; Forster, H.; Boersma, A.; Seiler, A.; Wehnes, H.; Sinowatz, F.; Neumuller, C.; Deutsch, M.J.; Walch, A.; Hrabe de Angelis, M.; et al. Mitochondrial glutathione peroxidase 4 disruption causes male infertility. FASEB J. 2009, 23, 3233–3242.
  54. Yant, L.J.; Ran, Q.; Rao, L.; Van Remmen, H.; Shibatani, T.; Belter, J.G.; Motta, L.; Richardson, A.; Prolla, T.A. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults. Free Radic. Biol. Med. 2003, 34, 496–502.
  55. Tadokoro, T.; Ikeda, M.; Ide, T.; Deguchi, H.; Ikeda, S.; Okabe, K.; Ishikita, A.; Matsushima, S.; Koumura, T.; Yamada, K.I.; et al. Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity. JCI Insight 2020, 5, e132747.
  56. Kitakata, H.; Endo, J.; Matsushima, H.; Yamamoto, S.; Ikura, H.; Hirai, A.; Koh, S.; Ichihara, G.; Hiraide, T.; Moriyama, H.; et al. MITOL/MARCH5 determines the susceptibility of cardiomyocytes to doxorubicin-induced ferroptosis by regulating GSH homeostasis. J. Mol. Cell Cardiol. 2021, 161, 116–129.
  57. Ta, N.; Qu, C.; Wu, H.; Zhang, D.; Sun, T.; Li, Y.; Wang, J.; Wang, X.; Tang, T.; Chen, Q.; et al. Mitochondrial outer membrane protein FUNDC2 promotes ferroptosis and contributes to doxorubicin-induced cardiomyopathy. Proc. Natl. Acad. Sci. USA 2022, 119, e2117396119.
  58. To, T.L.; Cuadros, A.M.; Shah, H.; Hung, W.H.W.; Li, Y.; Kim, S.H.; Rubin, D.H.F.; Boe, R.H.; Rath, S.; Eaton, J.K.; et al. A Compendium of Genetic Modifiers of Mitochondrial Dysfunction Reveals Intra-organelle Buffering. Cell 2019, 179, 1222–1238.e1217.
  59. Mao, C.; Liu, X.; Zhang, Y.; Lei, G.; Yan, Y.; Lee, H.; Koppula, P.; Wu, S.; Zhuang, L.; Fang, B.; et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 2021, 593, 586–590.
  60. Wu, S.; Mao, C.; Kondiparthi, L.; Poyurovsky, M.V.; Olszewski, K.; Gan, B. A ferroptosis defense mechanism mediated by glycerol-3-phosphate dehydrogenase 2 in mitochondria. Proc. Natl. Acad. Sci. USA 2022, 119, e2121987119.
  61. Doll, S.; Freitas, F.P.; Shah, R.; Aldrovandi, M.; da Silva, M.C.; Ingold, I.; Goya Grocin, A.; Xavier da Silva, T.N.; Panzilius, E.; Scheel, C.H.; et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 2019, 575, 693–698.
  62. Bersuker, K.; Hendricks, J.M.; Li, Z.; Magtanong, L.; Ford, B.; Tang, P.H.; Roberts, M.A.; Tong, B.; Maimone, T.J.; Zoncu, R.; et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 2019, 575, 688–692.
  63. Wang, Y.; Hekimi, S. Understanding Ubiquinone. Trends Cell Biol. 2016, 26, 367–378.
  64. Shimada, K.; Hayano, M.; Pagano, N.C.; Stockwell, B.R. Cell-Line Selectivity Improves the Predictive Power of Pharmacogenomic Analyses and Helps Identify NADPH as Biomarker for Ferroptosis Sensitivity. Cell Chem. Biol. 2016, 23, 225–235.
  65. Ding, C.C.; Rose, J.; Sun, T.; Wu, J.; Chen, P.H.; Lin, C.C.; Yang, W.H.; Chen, K.Y.; Lee, H.; Xu, E.; et al. MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nat. Metab. 2020, 2, 270–277.
  66. Koppula, P.; Lei, G.; Zhang, Y.; Yan, Y.; Mao, C.; Kondiparthi, L.; Shi, J.; Liu, X.; Horbath, A.; Das, M.; et al. A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers. Nat. Commun. 2022, 13, 2206.
  67. Venkatesh, D.; O’Brien, N.A.; Zandkarimi, F.; Tong, D.R.; Stokes, M.E.; Dunn, D.E.; Kengmana, E.S.; Aron, A.T.; Klein, A.M.; Csuka, J.M.; et al. MDM2 and MDMX promote ferroptosis by PPARalpha-mediated lipid remodeling. Genes Dev. 2020, 34, 526–543.
  68. Mishima, E.; Ito, J.; Wu, Z.; Nakamura, T.; Wahida, A.; Doll, S.; Tonnus, W.; Nepachalovich, P.; Eggenhofer, E.; Aldrovandi, M.; et al. A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 2022, 608, 778–783.
  69. Gan, B. Mitochondrial regulation of ferroptosis. J. Cell Biol. 2021, 220, e202105043.
  70. Kraft, V.A.N.; Bezjian, C.T.; Pfeiffer, S.; Ringelstetter, L.; Muller, C.; Zandkarimi, F.; Merl-Pham, J.; Bao, X.; Anastasov, N.; Kossl, J.; et al. GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. ACS Cent. Sci. 2020, 6, 41–53.
  71. Levine, A.J. p53: 800 million years of evolution and 40 years of discovery. Nat. Rev. Cancer 2020, 20, 471–480.
  72. Momand, J.; Jung, D.; Wilczynski, S.; Niland, J. The MDM2 gene amplification database. Nucleic. Acids. Res. 1998, 26, 3453–3459.
  73. Daver, N.G.; Maiti, A.; Kadia, T.M.; Vyas, P.; Majeti, R.; Wei, A.H.; Garcia-Manero, G.; Craddock, C.; Sallman, D.A.; Kantarjian, H.M. TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Biology, Current Therapy, and Future Directions. Cancer Discov. 2022, 12, 2516–2529.
  74. Jiang, L.; Kon, N.; Li, T.; Wang, S.J.; Su, T.; Hibshoosh, H.; Baer, R.; Gu, W. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 2015, 520, 57–62.
  75. Liu, D.S.; Duong, C.P.; Haupt, S.; Montgomery, K.G.; House, C.M.; Azar, W.J.; Pearson, H.B.; Fisher, O.M.; Read, M.; Guerra, G.R.; et al. Inhibiting the system xC−/glutathione axis selectively targets cancers with mutant-p53 accumulation. Nat. Commun. 2017, 8, 14844.
  76. Chu, B.; Kon, N.; Chen, D.; Li, T.; Liu, T.; Jiang, L.; Song, S.; Tavana, O.; Gu, W. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat. Cell Biol. 2019, 21, 579–591.
  77. Ou, Y.; Wang, S.J.; Li, D.; Chu, B.; Gu, W. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc. Natl. Acad. Sci. USA 2016, 113, E6806–E6812.
  78. Zhang, Y.; Qian, Y.; Zhang, J.; Yan, W.; Jung, Y.S.; Chen, M.; Huang, E.; Lloyd, K.; Duan, Y.; Wang, J.; et al. Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2. Genes Dev. 2017, 31, 1243–1256.
  79. Hu, W.; Zhang, C.; Wu, R.; Sun, Y.; Levine, A.; Feng, Z. Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc. Natl. Acad. Sci. USA 2010, 107, 7455–7460.
  80. Tarangelo, A.; Magtanong, L.; Bieging-Rolett, K.T.; Li, Y.; Ye, J.; Attardi, L.D.; Dixon, S.J. p53 Suppresses Metabolic Stress-Induced Ferroptosis in Cancer Cells. Cell Rep. 2018, 22, 569–575.
  81. Chen, D.; Chu, B.; Yang, X.; Liu, Z.; Jin, Y.; Kon, N.; Rabadan, R.; Jiang, X.; Stockwell, B.R.; Gu, W. iPLA2beta-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4. Nat. Commun. 2021, 12, 3644.
  82. Kuganesan, N.; Dlamini, S.; Tillekeratne, L.M.V.; Taylor, W.R. Tumor suppressor p53 promotes ferroptosis in oxidative stress conditions independent of modulation of ferroptosis by p21, CDKs, RB, and E2F. J. Biol. Chem. 2021, 297, 101365.
  83. Kang, R.; Kroemer, G.; Tang, D. The tumor suppressor protein p53 and the ferroptosis network. Free Radic. Biol. Med. 2019, 133, 162–168.
  84. Ji, H.; Wang, W.; Li, X.; Han, X.; Zhang, X.; Wang, J.; Liu, C.; Huang, L.; Gao, W. p53: A double-edged sword in tumor ferroptosis. Pharm. Res. 2022, 177, 106013.
  85. Liu, Y.; Gu, W. p53 in ferroptosis regulation: The new weapon for the old guardian. Cell Death Differ. 2022, 29, 895–910.
  86. Armand, P.; Kim, H.T.; Rhodes, J.; Sainvil, M.M.; Cutler, C.; Ho, V.T.; Koreth, J.; Alyea, E.P.; Hearsey, D.; Neufeld, E.J.; et al. Iron overload in patients with acute leukemia or MDS undergoing myeloablative stem cell transplantation. Biol. Blood. Marrow. Transpl. 2011, 17, 852–860.
  87. Kautz, L.; Nemeth, E. Molecular liaisons between erythropoiesis and iron metabolism. Blood 2014, 124, 479–482.
  88. Atilla, E.; Toprak, S.K.; Demirer, T. Current Review of Iron Overload and Related Complications in Hematopoietic Stem Cell Transplantation. Turk. J. Haematol. 2017, 34, 1–9.
  89. Wermke, M.; Eckoldt, J.; Gotze, K.S.; Klein, S.A.; Bug, G.; de Wreede, L.C.; Kramer, M.; Stolzel, F.; von Bonin, M.; Schetelig, J.; et al. Enhanced labile plasma iron and outcome in acute myeloid leukaemia and myelodysplastic syndrome after allogeneic haemopoietic cell transplantation (ALLIVE): A prospective, multicentre, observational trial. Lancet Haematol. 2018, 5, e201–e210.
  90. Lopes, M.; Duarte, T.L.; Teles, M.J.; Mosteo, L.; Chacim, S.; Aguiar, E.; Pereira-Reis, J.; Oliveira, M.; Silva, A.M.N.; Goncalves, N.; et al. Loss of erythroblasts in acute myeloid leukemia causes iron redistribution with clinical implications. Blood. Adv. 2021, 5, 3102–3112.
  91. Liu, Q.; Wang, M.; Hu, Y.; Xing, H.; Chen, X.; Zhang, Y.; Zhu, P. Significance of CD71 expression by flow cytometry in diagnosis of acute leukemia. Leuk. Lymphoma 2014, 55, 892–898.
  92. Gasparetto, M.; Pei, S.; Minhajuddin, M.; Stevens, B.; Smith, C.A.; Seligman, P. Low ferroportin expression in AML is correlated with good risk cytogenetics, improved outcomes and increased sensitivity to chemotherapy. Leuk. Res. 2019, 80, 1–10.
  93. Trujillo-Alonso, V.; Pratt, E.C.; Zong, H.; Lara-Martinez, A.; Kaittanis, C.; Rabie, M.O.; Longo, V.; Becker, M.W.; Roboz, G.J.; Grimm, J.; et al. FDA-approved ferumoxytol displays anti-leukaemia efficacy against cells with low ferroportin levels. Nat. Nanotechnol. 2019, 14, 616–622.
  94. Zhou, N.; Bao, J. FerrDb: A manually curated resource for regulators and markers of ferroptosis and ferroptosis-disease associations. Database 2020, 2020, baaa021.
  95. Zhou, N.; Yuan, X.; Du, Q.; Zhang, Z.; Shi, X.; Bao, J.; Ning, Y.; Peng, L. FerrDb V2: Update of the manually curated database of ferroptosis regulators and ferroptosis-disease associations. Nucleic. Acids. Res. 2023, 51, D571–D582.
  96. Handschuh, L. Not Only Mutations Matter: Molecular Picture of Acute Myeloid Leukemia Emerging from Transcriptome Studies. J. Oncol. 2019, 2019, 7239206.
  97. Wei, J.; Nai, G.Y.; Dai, Y.; Huang, X.J.; Xiong, M.Y.; Yao, X.Y.; Huang, Z.N.; Li, S.N.; Zhou, W.J.; Huang, Y.; et al. Dipetidyl peptidase-4 and transferrin receptor serve as prognostic biomarkers for acute myeloid leukemia. Ann. Transl. Med. 2021, 9, 1381.
  98. Shao, R.; Wang, H.; Liu, W.; Wang, J.; Lu, S.; Tang, H.; Lu, Y. Establishment of a prognostic ferroptosis-related gene profile in acute myeloid leukaemia. J. Cell Mol. Med. 2021, 25, 10950–10960.
  99. Huang, X.; Zhou, D.; Ye, X.; Jin, J. A novel ferroptosis-related gene signature can predict prognosis and influence immune microenvironment in acute myeloid leukemia. Bosn. J. Basic. Med. Sci. 2022, 22, 608–628.
  100. Song, Y.; Tian, S.; Zhang, P.; Zhang, N.; Shen, Y.; Deng, J. Construction and Validation of a Novel Ferroptosis-Related Prognostic Model for Acute Myeloid Leukemia. Front. Genet. 2021, 12, 708699.
  101. Cui, Z.; Fu, Y.; Yang, Z.; Gao, Z.; Feng, H.; Zhou, M.; Zhang, L.; Chen, C. Comprehensive Analysis of a Ferroptosis Pattern and Associated Prognostic Signature in Acute Myeloid Leukemia. Front. Pharm. 2022, 13, 866325.
  102. Zheng, Z.; Hong, X.; Huang, X.; Jiang, X.; Jiang, H.; Huang, Y.; Wu, W.; Xue, Y.; Lin, D. Comprehensive analysis of ferroptosis-related gene signatures as a potential therapeutic target for acute myeloid leukemia: A bioinformatics analysis and experimental verification. Front. Oncol. 2022, 12, 930654.
  103. Wang, J.; Zhuo, Z.; Wang, Y.; Yang, S.; Chen, J.; Wang, Y.; Geng, S.; Li, M.; Du, X.; Lai, P.; et al. Identification and Validation of a Prognostic Risk-Scoring Model Based on Ferroptosis-Associated Cluster in Acute Myeloid Leukemia. Front. Cell Dev. Biol. 2021, 9, 800267.
  104. Zhu, K.; Lang, Z.; Zhan, Y.; Tao, Q.; Yu, Z.; Chen, L.; Fan, C.; Jin, Y.; Yu, K.; Zhu, B.; et al. A novel 10-gene ferroptosis-related prognostic signature in acute myeloid leukemia. Front. Oncol. 2022, 12, 1023040.
  105. Hong, Y.; Zhang, L.; Tian, X.; Xiang, X.; Yu, Y.; Zeng, Z.; Cao, Y.; Chen, S.; Sun, A. Identification of immune subtypes of Ph-neg B-ALL with ferroptosis related genes and the potential implementation of Sorafenib. BMC Cancer 2021, 21, 1331.
  106. Gong, H.; Li, H.; Yang, Q.; Zhang, G.; Liu, H.; Ma, Z.; Peng, H.; Nie, L.; Xiao, X.; Liu, J. A Ferroptosis Molecular Subtype-Related Signature for Predicting Prognosis and Response to Chemotherapy in Patients with Chronic Lymphocytic Leukemia. Biomed. Res. Int. 2022, 2022, 5646275.
  107. Pan, B.; Li, Y.; Xu, Z.; Miao, Y.; Yin, H.; Kong, Y.; Zhang, X.; Liang, J.; Xia, Y.; Wang, L.; et al. Identifying a novel ferroptosis-related prognostic score for predicting prognosis in chronic lymphocytic leukemia. Front. Immunol. 2022, 13, 962000.
  108. Zhou, F.; Chen, B. Prognostic significance of ferroptosis-related genes and their methylation in AML. Hematology 2021, 26, 919–930.
  109. Han, C.; Zheng, J.; Li, F.; Guo, W.; Cai, C. Novel Prognostic Signature for Acute Myeloid Leukemia: Bioinformatics Analysis of Combined CNV-Driven and Ferroptosis-Related Genes. Front. Genet. 2022, 13, 849437.
  110. Zheng, Z.; Wu, W.; Lin, Z.; Liu, S.; Chen, Q.; Jiang, X.; Xue, Y.; Lin, D. Identification of seven novel ferroptosis-related long non-coding RNA signatures as a diagnostic biomarker for acute myeloid leukemia. BMC Med. Genom. 2021, 14, 236.
  111. Tao, Y.; Wei, L.; You, H. Ferroptosis-related gene signature predicts the clinical outcome in pediatric acute myeloid leukemia patients and refines the 2017 ELN classification system. Front. Mol. Biosci. 2022, 9, 954524.
  112. Yu, Y.; Xie, Y.; Cao, L.; Yang, L.; Yang, M.; Lotze, M.T.; Zeh, H.J.; Kang, R.; Tang, D. The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents. Mol. Cell Oncol. 2015, 2, e1054549.
  113. Ye, F.; Chai, W.; Xie, M.; Yang, M.; Yu, Y.; Cao, L.; Yang, L. HMGB1 regulates erastin-induced ferroptosis via RAS-JNK/p38 signaling in HL-60/NRAS(Q61L) cells. Am. J. Cancer Res. 2019, 9, 730–739.
  114. Zhu, T.; Liu, B.; Wu, D.; Xu, G.; Fan, Y. Autophagy Regulates VDAC3 Ubiquitination by FBXW7 to Promote Erastin-Induced Ferroptosis in Acute Lymphoblastic Leukemia. Front. Cell Dev. Biol. 2021, 9, 740884.
  115. Lalonde, M.E.; Sasseville, M.; Gelinas, A.M.; Milanese, J.S.; Beland, K.; Drouin, S.; Haddad, E.; Marcotte, R. Genome-wide CRISPR screens identify ferroptosis as a novel therapeutic vulnerability in acute lymphoblastic leukemia. Haematologica 2023, 108, 382–393.
  116. Liu, S.; Wu, W.; Chen, Q.; Zheng, Z.; Jiang, X.; Xue, Y.; Lin, D. TXNRD1: A Key Regulator Involved in the Ferroptosis of CML Cells Induced by Cysteine Depletion In Vitro. Oxid. Med. Cell Longev. 2021, 2021, 7674565.
  117. Lv, Q.; Niu, H.; Yue, L.; Liu, J.; Yang, L.; Liu, C.; Jiang, H.; Dong, S.; Shao, Z.; Xing, L.; et al. Abnormal Ferroptosis in Myelodysplastic Syndrome. Front. Oncol. 2020, 10, 1656.
  118. Wang, X.; Liu, X.; Wang, H. Combination regimen of granulocyte colony-stimulating factor and recombinant human thrombopoietin improves the curative effect on elderly patients with leukemia through inducing pyroptosis and ferroptosis of leukemia cells. Cancer Gene 2022, 29, 1742–1750.
  119. Birsen, R.; Larrue, C.; Decroocq, J.; Johnson, N.; Guiraud, N.; Gotanegre, M.; Cantero-Aguilar, L.; Grignano, E.; Huynh, T.; Fontenay, M.; et al. APR-246 induces early cell death by ferroptosis in acute myeloid leukemia. Haematologica 2022, 107, 403–416.
  120. Bruedigam, C.; Porter, A.H.; Song, A.; Vroeg in de Wei, G.; Stoll, T.; Straube, J.; Cooper, L.T.; Cheng, G.; Kahl, V.F.; Sobinoff, A.; et al. Imetelstat-Mediated Alterations in Lipid Metabolism to Induce Ferroptosis As Therapeutic Strategy for Acute Myeloid Leukemia. Blood 2022, 140, 487–488.
  121. Ma, H.; Liu, Y.; Miao, Z.; Cheng, S.; Zhu, Y.; Wu, Y.; Fan, X.; Yang, J.; Li, X.; Guo, L. Neratinib inhibits proliferation and promotes apoptosis of acute myeloid leukemia cells by activating autophagy-dependent ferroptosis. Drug Dev. Res. 2022, 83, 1641–1653.
  122. Du, J.; Wang, T.; Li, Y.; Zhou, Y.; Wang, X.; Yu, X.; Ren, X.; An, Y.; Wu, Y.; Sun, W.; et al. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic. Biol. Med. 2019, 131, 356–369.
  123. Zhu, H.Y.; Huang, Z.X.; Chen, G.Q.; Sheng, F.; Zheng, Y.S. Typhaneoside prevents acute myeloid leukemia (AML) through suppressing proliferation and inducing ferroptosis associated with autophagy. Biochem. Biophys. Res. Commun. 2019, 516, 1265–1271.
  124. Lou, S.; Hong, H.; Maihesuti, L.; Gao, H.; Zhu, Z.; Xu, L.; Tian, S.; Kai, G.; Huang, G.; Zhao, H. Inhibitory effect of hydnocarpin D on T-cell acute lymphoblastic leukemia via induction of autophagy-dependent ferroptosis. Exp. Biol. Med. Maywood 2021, 246, 1541–1553.
  125. Catanzaro, E.; Turrini, E.; Kerre, T.; Sioen, S.; Baeyens, A.; Guerrini, A.; Abdi Bellau, M.L.; Sacchetti, G.; Paganetto, G.; Krysko, D.V.; et al. Perillaldehyde is a new ferroptosis inducer with a relevant clinical potential for acute myeloid leukemia therapy. Biomed. Pharmacother. 2022, 154, 113662.
  126. Li, Q.; Su, R.; Bao, X.; Cao, K.; Du, Y.; Wang, N.; Wang, J.; Xing, F.; Yan, F.; Huang, K.; et al. Glycyrrhetinic acid nanoparticles combined with ferrotherapy for improved cancer immunotherapy. Acta Biomater. 2022, 144, 109–120.
  127. Greco, G.; Schnekenburger, M.; Catanzaro, E.; Turrini, E.; Ferrini, F.; Sestili, P.; Diederich, M.; Fimognari, C. Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential. Cancers 2021, 14, 76.
  128. Lai, X.; Sun, Y.; Zhang, X.; Wang, D.; Wang, J.; Wang, H.; Zhao, Y.; Liu, X.; Xu, X.; Song, H.; et al. Honokiol Induces Ferroptosis by Upregulating HMOX1 in Acute Myeloid Leukemia Cells. Front. Pharm. 2022, 13, 897791.
  129. Du, Y.; Bao, J.; Zhang, M.J.; Li, L.L.; Xu, X.L.; Chen, H.; Feng, Y.B.; Peng, X.Q.; Chen, F.H. Targeting ferroptosis contributes to ATPR-induced AML differentiation via ROS-autophagy-lysosomal pathway. Gene 2020, 755, 144889.
  130. Chen, L.; Fang, W.; Liu, J.; Qi, X.; Zhao, L.; Wang, Y.; Liu, Y.; Kong, D.; Sun, X.; Li, X.; et al. Poricoic acid A (PAA) inhibits T-cell acute lymphoblastic leukemia through inducing autophagic cell death and ferroptosis. Biochem. Biophys. Res. Commun. 2022, 608, 108–115.
  131. Yusuf, R.Z.; Saez, B.; Sharda, A.; van Gastel, N.; Yu, V.W.C.; Baryawno, N.; Scadden, E.W.; Acharya, S.; Chattophadhyay, S.; Huang, C.; et al. Aldehyde dehydrogenase 3a2 protects AML cells from oxidative death and the synthetic lethality of ferroptosis inducers. Blood 2020, 136, 1303–1316.
  132. Du, Y.; Han, M.; Cao, K.; Li, Q.; Pang, J.; Dou, L.; Liu, S.; Shi, Z.; Yan, F.; Feng, S. Gold Nanorods Exhibit Intrinsic Therapeutic Activity via Controlling N6-Methyladenosine-Based Epitranscriptomics in Acute Myeloid Leukemia. ACS Nano 2021, 15, 17689–17704.
  133. Wang, Z.; Chen, X.; Liu, N.; Shi, Y.; Liu, Y.; Ouyang, L.; Tam, S.; Xiao, D.; Liu, S.; Wen, F.; et al. A Nuclear Long Non-Coding RNA LINC00618 Accelerates Ferroptosis in a Manner Dependent upon Apoptosis. Mol Ther. 2021, 29, 263–274.
  134. Dong, L.H.; Huang, J.J.; Zu, P.; Liu, J.; Gao, X.; Du, J.W.; Li, Y.F. CircKDM4C upregulates P53 by sponging hsa-let-7b-5p to induce ferroptosis in acute myeloid leukemia. Environ. Toxicol. 2021, 36, 1288–1302.
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