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Role of Ferroptosis in AML Pathophysiology and Therapeutic Strategies

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Gregorio Favale, Vincenza Capone, Daniela Carannante, Giulia Verrilli, Antonio Beato, Fatima Fayyaz, Rosaria Benedetti, Lucia Altucci and Vincenzo Carafa

Submitted: 21 February 2025 Reviewed: 29 May 2025 Published: 24 June 2025

DOI: 10.5772/intechopen.1011347

Cell Death Regulation in Pathology IntechOpen
Cell Death Regulation in Pathology Edited by Vincenzo Carafa

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Cell Death Regulation in Pathology [Working Title]

Vincenzo Carafa

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Abstract

Ferroptosis, an iron-dependent form of regulated cell death marked by lipid peroxidation, is critically implicated in the pathology of acute myeloid leukemia (AML). The dysregulation of iron metabolism and ferroptotic regulators, such as GPX4, the cystine/glutamate antiporter System Xc−, and several iron homeostasis proteins, contributes to leukemic cell survival and therapy resistance. These disruptions not only facilitate the survival and proliferation of leukemic cells but also enable them to evade traditional apoptotic pathways, thereby increasing resistance to standard therapeutic interventions. Recent studies have focused on identifying specific targets within the ferroptosis pathway that are aberrantly expressed in AML, highlighting potential vulnerabilities that can be exploited for therapeutic benefit. Promising compounds such as Erastin and RSL3 have emerged as effective inducers of ferroptosis in AML cells, demonstrating the capacity to circumvent resistance mechanisms. These agents function by inhibiting GPX4 and disrupting cystine uptake, which culminates in enhanced lipid peroxidation and cell death. This chapter explores the therapeutic potential of targeting ferroptosis in AML, with a particular focus on modulating iron metabolism and key regulatory pathways. By exploiting the vulnerabilities in ferroptotic processes, these strategies offer a novel approach to enhancing therapeutic efficacy and addressing the critical challenge of drug resistance in AML.

Keywords

  • AML
  • ferroptosis
  • therapy
  • cell death
  • drug discovery

1. Introduction

Acute myeloid leukemia (AML) is a highly aggressive blood cancer defined by the clonal proliferation of myeloid progenitor cells that are either undifferentiated or poorly differentiated. This expansion disrupts normal hematopoiesis leading to significant bone marrow failure and various complications [1]. The pathogenesis of AML is driven by a complex interplay of genetic and epigenetic alterations, including chromosomal rearrangements such as translocations (e.g., t(8; 21), t(15; 17)), and inversions (e.g., inv(16)), along with somatic mutations in key genes (FLT3, NPM1, IDH1/2, DNMT3A, and TET2) and dysregulation of transcriptional and epigenetic machinery [2]. These molecular aberrations orchestrate a pathogenic cascade that impairs differentiation, promotes uncontrolled proliferation, and ultimately leads to leukemic transformation. Despite significant advancements in the characterization of the molecular landscape of AML and the development of targeted therapies, clinical outcomes continue to be unsatisfactory. AML originates from the myeloid lineage of hematopoietic stem cells and is characterized by the rapid expansion of immature leukemic blasts that replace normal hematopoietic tissue within the bone marrow. This replacement leads to disruption of the bone marrow microenvironment and a blockage in progenitor cell differentiation and maturation at various developmental stages [3, 4]. The incidence of AML has been rising in the time, and despite recent advancements in therapy, the mortality rate remains high due to its aggressiveness and frequent relapses [3]. One of the hallmark features of AML is its capacity to escape programmed cell death, a pivotal mechanism for preserving cellular balance and removing cells with oncogenic potential. Evasion of cell death contributes to the aggressive nature of AML as well as facilitates disease progression and therapeutic resistance [3]. Apoptosis, the most extensively characterized form of regulated cell death, has been a central focus in AML research and therapeutic development. Apoptotic pathways are activated via intrinsic or extrinsic signals that converge on caspase-mediated cellular breaking down. However, AML frequently exhibits resistance to apoptosis through multiple mechanisms, including the overexpression of anti-apoptotic proteins, such as B-cell leukemia/lymphoma 2 protein (BCL-2), c-1 (MCL1), and B-cell lymphoma-extra large (BCL-XL), mutations in tumor suppressor genes like TP53, and dysregulated signaling in survival pathways such as phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [5, 6]. These adaptations limit the efficacy of chemotherapeutic agents and reduce the impact of apoptosis-targeted drugs, such as venetoclax, highlighting the necessity for alternative therapeutic approaches. The challenges associated with apoptosis-based therapies have prompted interest in investigating alternative forms of regulated cell death (RCD) [6]. Among these, ferroptosis has emerged as a particularly promising area of investigation in AML. Unlike apoptosis, ferroptosis is not mediated by caspases but is instead governed by disruptions in redox balance, iron metabolism, and lipid homeostasis. Mechanistically, ferroptosis is initiated by oxidative stress and the failure of the glutathione peroxidase 4 (GPX4)-dependent antioxidant defense system, which results in uncontrolled lipid peroxidation [3]. This process is further exacerbated by the intrinsic metabolic alterations of AML, which allow cells to adapt to increased levels of reactive oxygen species (ROS) by avoiding apoptosis. Additionally, the increased absorption and storage of iron enhance susceptibility to ferroptotic cell death, especially under conditions of oxidative stress [7]. This emergent cell death has also been implicated in modulating the tumor microenvironment, suggesting that its induction may not only eradicate leukemic cells but also reprogram the environment to favor immune-mediated clearance. Furthermore, iron metabolism plays a crucial role in the context of ferroptosis, as an essential element for ROS production through Fenton reactions [7]. In particular, AML cells exhibit increased iron uptake and storage, driven by overexpression of iron-regulatory players such as transferrin receptor 1 (TFR1) and ferritin [3, 8]. Inducers such as erastin (which inhibits cystine import via SLC7A11) and RSL3 (which directly inhibits GPX4) have shown promise in selectively inducing ferroptosis in AML cells while sparing normal hematopoietic stem cells [9, 10]. Inducers such as erastin (which inhibits cystine import via SLC7A11) and RSL3 (which directly inhibits GPX4) have shown promise in selectively inducing ferroptosis in AML cells while sparing normal hematopoietic stem cells. These agents have demonstrated synergism with traditional AML drugs such as anthracyclines (Anth) and cytarabine (Ara-C), enhancing cytotoxicity by exacerbating oxidative stress. Moreover, high expression of SLC7A11 and GPX4 has been identified as a poor prognostic marker in AML, highlighting their potential both as therapeutic targets and biomarkers [3]. These evidences highlight the therapeutic role of ferroptosis as a modality to eradicate minimal residual disease and reduce the risk of relapse in AML patients [11]. The unique metabolic profile of AML cells, including their reliance on aberrant lipid biosynthesis and oxidation, creates vulnerabilities that can be exploited through ferroptosis induction. Disruption of lipid signaling pathways, such as those involving acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3), has been shown to enhance ferroptosis sensitivity. Similarly, targeting nuclear factor erythroid 2-related factor 2 (NRF2)-mediated antioxidant responses, which often confer resistance to ferroptosis in leukemic cells, represents another promising strategy [12, 13]. The intersection of these metabolic and signaling pathways offers a comprehensive framework for designing combination therapies that enhance ferroptosis while simultaneously addressing other hallmarks of AML pathogenesis. This chapter aims to deliver an analysis of the pathogenetic mechanisms underlying AML, with a focus on the dysregulation of cell death pathways and the therapeutic potential of ferroptosis. The elucidation of these interconnected processes not only advances our understanding of AML biology but also paves the way for novel therapeutic approaches to overcome treatment resistance and improve patient outcomes.

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2. Ferroptosis: Molecular mechanisms and regulation

The maintenance of cellular homeostasis in multicellular organisms is orchestrated by intricate regulatory networks that control metabolic processes and mitigate the accumulation of reactive byproducts. Among these, ROS proteins, nucleic acids, and lipids are primary targets, with the latter being especially vulnerable due to their structural role in cellular membranes [14]. Polyunsaturated fatty acids (PUFAs) in phospholipids are particularly susceptible to lipid peroxidation, a chain reaction initiated by ROS and catalyzed by enzymes such as lipoxygenases (LOXs). These iron-dependent enzymes abstract hydrogen atoms from lipid C‒H bonds, perpetuating ROS propagation and leading to the formation of lipid hydroperoxides. If unchecked, this process disrupts membrane integrity and culminates in ferroptosis, a unique, iron-dependent form of regulated cell death. Ferroptosis is intrinsically linked to iron metabolism [15]. The availability of free, catalytically active iron amplifies ROS generation through Fenton chemistry, wherein ferrous iron (Fe2+) reacts with hydrogen peroxide (H2O2) to form hydroxyl radicals, potent inducers of lipid peroxidation [16]. To counteract this lethal cascade, cells trigger the activation of several antioxidant mechanisms. System Xc−, a heterodimer consisting of SLC7A11 (xCT) and SLC3A2 (CD98), mediates the import of extracellular cystine in exchange for intracellular glutamate. Once inside the cell, cystine is reduced to cysteine, which is necessary for the GSH production, the primary cofactor for GPX4. This enzyme neutralizes lipid hydroperoxides by converting them into nontoxic lipid alcohols, thereby preserving membrane integrity and preventing ferroptosis [17]. Moreover, intracellular cystine levels induce the mammalian target of rapamycin complex 1 (mTORC1), which enhances GPX4 synthesis, further improving cellular defenses against lipid peroxidation [18]. Recent findings have also highlighted the role of ferroptosis suppressor protein 1 (FSP1), an oxidoreductase that acts independently of GPX4 by reducing coenzyme Q10 (CoQ10) to ubiquinol, a lipophilic antioxidant that traps lipid radicals in membranes and prevents lipid peroxidation. This GPX4-independent mechanism adds another layer of protection against ferroptosis and may serve as a complementary or alternative therapeutic target in contexts where GPX4 is impaired [3]. Ferroptosis plays a critical role in several pathological conditions, such as neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis), ischemia-reperfusion injury (e.g., myocardial infarction and stroke), acute kidney injury, and liver disorders (nonalcoholic fatty liver disease and alcoholic liver disease). Additionally, targeting ferroptosis therapeutically is emerging as a potential strategy for cancer treatment [19]. Tumor cells frequently exhibit alterations in iron metabolism, including upregulated iron import and storage pathways, alongside impaired antioxidant mechanisms, which render them particularly susceptible to ferroptosis [20].

Ferroptosis-inducing agents such as erastin and RSL3 are currently under preclinical and clinical investigation, particularly for their ability to overcome chemoresistance in malignancies like AML. Moreover, combinatorial approaches that couple ferroptosis inducers with immunotherapies are being explored to amplify antitumor immune responses [3]. Selective targeting of key ferroptosis players, such as system Xc− and GPX4, allows for the induction of cancer cell death while sparing normal tissues. This approach not only exploits the unique vulnerabilities of tumor cells but also enhances the efficacy of existing therapies, including chemotherapy and immunotherapy. By integrating ferroptosis in therapeutic strategies, it may be possible to overcome treatment resistance and improve clinical outcomes for patients with aggressive or refractory malignancies [21]. Elucidating the molecular interplay between iron metabolism, ROS generation, and antioxidant defenses could pave the way for novel interventions aimed at modulating ferroptosis in a context-specific manner, thus addressing a wide array of human diseases.

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3. Dysregulation of ferroptosis in AML

Ferroptosis has emerged as a pivotal mechanism of cell death in AML. Leukemia cells exhibit distinctive metabolic and genetic adaptations that heighten their vulnerability to ferroptosis while simultaneously developing mechanisms to evade this process, thereby supporting their survival and progression [22]. Mitochondrial metabolism plays a central role in AML cell bioenergetics, serving as the primary source of ROS and oxidative phosphorylation (OXPHOS). AML cells rely heavily on mitochondrial metabolism and show a significant increase in mitochondrial mass when compared to normal hematopoietic stem cells [23]. While AML cells display limited metabolic flexibility, favoring glycolysis over fatty acid oxidation, their dependence on mitochondrial respiration renders them susceptible to ROS-induced damage and lipid peroxidation, key processes in ferroptosis (Figure 1). ROS, which are elevated in many malignancies, have a dual role in AML; high ROS levels can enhance chemotherapeutic efficacy by inducing apoptosis, whereas low levels support cell survival, proliferation, and drug resistance [23, 24].

Figure 1.

Key dysregulated processes related to ferroptosis in AML cells. The image highlights major cellular pathways implicated in ferroptosis, including iron metabolism, lipid peroxidation, antioxidant defense, and mitochondrial function.

In AML, ROS overproduction arises not only from mitochondrial metabolism but also from altered enzymatic pathways, including xanthine oxidoreductase, nitric oxide synthase, and cytochrome P450 monooxygenase. Moreover, the NOX family of NADPH oxidases (NOXs), particularly NOX2 and NOX4, is frequently overexpressed, with NOX2 constitutively producing extracellular superoxide in approximately 60% of patients. This chronic ROS generation contributes to leukemic progression and ferroptosis susceptibility (Figure 1) [3].

Targeting NOX2 has been shown to improve the efficacy of oxidative stress-inducing agents, highlighting its potential as a therapeutic target [3]. AML cells have also evolved mechanisms to regulate ROS levels and mitigate oxidative stress, including the activation of antioxidant pathways such as the NRF2 pathway. Increased NRF2 expression is associated with drug resistance and poor clinical outcomes. A significant contributor to iron overload in AML is the frequent transfusion of red blood cells (RBCs) administered during chemotherapy. Transfused RBCs release iron, which is subsequently recycled and stored by macrophages in the liver and spleen, leading to the accumulation of unstable iron reserves [25]. At diagnosis, patients with AML often present with elevated serum ferritin levels, which correlate with tumor burden. These levels typically normalize following remission but may rise again during relapse. The transferrin (TF) system and TFR are critical for intracellular iron transport and represent the primary pathway through which tumor cells acquire iron. This mechanism is particularly important in inducing ferroptosis under conditions of glutamine depletion. AML cells demonstrate a strong affinity for TF and overexpress TFR, though the precise role of TFR in AML cells remains incompletely understood. TFR is essential for ferroptosis, as illustrated by findings that RAS-mutated cells with TFR overexpression accumulate intracellular iron and become more susceptible to ferroptosis induced by erastin [26]. Conversely, deletion of TFR reduces sensitivity to ferroptosis. Two isoforms of TFR exist: TFR1 and TFR2. TFR1 facilitates iron entry via receptor-mediated endocytosis through NCOA4 and serves as a validated marker of ferroptosis [27]. AML cells exhibit significantly higher TFR1 expression than normal cells, with levels increasing alongside malignancy differentiation. Elevated TFR1 expression has been linked to anemia, thrombocytopenia, and complex cytogenetics in AML, although it does not predict poor prognosis. In contrast, higher TFR2 mRNA expression in bone marrow samples of patients with AML or myelodysplastic syndromes (MDS) correlates with improved prognoses, suggesting a role for TFR2 in modulating iron metabolism and enhancing chemosensitivity [28]. The ferritin-ferroportin (FPN) axis serves as a key regulator of iron homeostasis and redox balance. Ferritin, composed of ferritin heavy chain (FTH) and ferritin light chain (FTL), stabilizes the labile plasma iron pool and inhibits ferroptosis by preventing iron efflux. Ferritin deficiency, however, reduces the regulatory activity of xCT and promotes ferroptosis. Both FTH and FTL are overexpressed in AML cells and leukemic stem cells (LSCs) compared to normal hematopoietic stem cells, with FTH overexpression often associated with NF-κB activation and decreased chemosensitivity. Consequently, elevated ferritin levels serve as markers of disease progression [3]. FPN, the primary axis governing intracellular iron efflux, inhibits tumor growth by lowering intracellular iron levels. In AML, FPN expression is strongly reduced respect to normal cells, and certain leukemic lines show severe downregulation. AML cells with low FPN expression accumulate more iron, rendering them more vulnerable to ROS. Studies using iron oxide nanoparticles in AML cells with low FPN expression have demonstrated enhanced antileukemic activity, further supporting the relationship between intracellular iron and chemotherapy sensitivity [29]. Additionally, reduced FPN levels in AML are frequently linked to elevated inflammatory cytokines, such as interleukin-6 (IL-6), contributing to dysfunctional iron metabolism and increased ferroptosis susceptibility [30]. Iron overload in AML and MDS patients has been evaluated using methods like biomagnetism, magnetic resonance imaging, and organ biopsies, revealing significant iron accumulation. This iron excess, along with heme, disrupts hematopoietic stem cell function in the bone marrow via ROS pathways, often necessitating additional blood transfusions and creating a pathological feedback loop (Figure 1) [31].

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4. Ferroptosis as therapeutic strategy against AML

The modulation of ferroptosis-related processes in the context of AML represents one of the most challenging aspects of developing therapeutic alternatives to counteract the high rates of mortality, relapse, and resistance to standard treatments [32]. Identifying dysregulated metabolic mechanisms specific to AML neoplastic clones offers significant potential for ferroptosis-inducing strategies. These approaches aim to selectively activate molecular pathways of regulated cell death while restoring proper hematopoietic processes in the bone marrow and minimizing damage to healthy cells [33]. Although the antioxidant defenses of cancer cells are constitutively active to support survival and prevent cell death activation, the increased iron uptake observed in AML clones triggers lipid peroxidation mechanisms in cellular membranes. This suggests a heightened susceptibility to ferroptosis induction, paving the way for strategies targeting key nodes within the ferroptosis pathway, such as lipid metabolism, redox balance, and autophagy (Figure 2) [3]. The reported multi-targeted approach not only improves the therapeutic effectiveness of ferroptosis induction but also holds promise for overcoming resistance to conventional therapies.

Figure 2.

Graphical overview illustrating key molecular mechanisms involved in ferroptosis. Pharmacological inducers of ferroptosis target critical regulators such as system Xc−, GPX4, and iron homeostasis pathways, promoting oxidative damage and cell death in AML cells.

4.1 Direct and indirect acting compounds on ferroptosis

Erastin, a well-characterized inhibitor of the system Xc−, exerts its biological effects by disrupting cystine and iron uptake and inhibiting GPX4 activity, ultimately triggering ferroptosis [34]. In the context of AML, erastin has been shown to activate the jun N-terminal kinase (JNK)/p38 molecular axis and promote the nuclear translocation of high mobility group box 1 protein (HMGB1), a key mediator in the production of ROS and the induction of ferroptosis. Furthermore, erastin demonstrates significant synergy with conventional chemotherapeutic agents such as Ara-C and doxorubicin (DXR), enhancing their antitumor efficacy [35]. Additionally, APR-246, initially known for reactivating mutant TP53, has been shown to induce ferroptosis by decreasing intracellular GSH and promoting lipid peroxidation, broadening its therapeutic potential beyond TP53-mutated AML cells [3, 36]. This therapeutic activity is evident both as monotherapy and when combined with GPX4 inhibitors, such as RSL3 and FINO2, further amplifying its ferroptotic effects. However, phase II clinical trials have reported significant neurological adverse events, with over one-third of patients experiencing these side effects [36].

The lipidomic analysis conducted on AML cells following treatment with the telomerase inhibitor imetelstat (GRN163L) demonstrates a marked increase in the levels of PUFAs, mediated by a fatty acid desaturase 2 (FADS2)-dependent mechanism [37]. FADS2 plays a crucial role by facilitating the desaturation of polyunsaturated fatty acids, particularly linoleic acid. This significant accumulation of peroxidation substrates subsequently activates ferroptosis, a form of regulated cell death, both in vitro and in xenograft models. These findings highlight the potential for targeting lipid metabolism as a therapeutic strategy in AML, opening avenues for future clinical applications in patients with this aggressive hematological malignancy [37]. In the regulation of the ferroptosis process, NRF2 is known to induce the expression of the cystine antiporter subunit xCT, thereby inhibiting iron oxidation through GSH-dependent GPX4 activity and promoting resistance to cell death [38]. Notably, AML patients exhibit higher levels of NRF2 compared to healthy controls, suggesting the oncogenic role of this protein. The use of the specific NRF2 inhibitor, ML385, weakens the antioxidant defenses of leukemic clones, inducing ferroptosis in combination with the chemotherapeutic agent venetoclax [39]. Sulfasalazine, an anti-inflammatory drug, induces ferroptosis in cancer cells by inhibiting SLC7A11 and preventing GSH synthesis, and its combination with anthracyclines enhances antileukemic activity [3]. In addition, all-trans retinoic acid (ATRA), which is known to promote the differentiation of leukemic cells, induces ferroptosis by downregulating NRF2 [40]. Bithionol, a well-established anthelmintic drug, has also been employed as an antibacterial agent and in the treatment of Alzheimer’s disease [41]. Recent studies have highlighted its potential for novel therapeutic applications, including the inhibition of NF-κB nuclear translocation and the induction of mitochondrial oxidative processes. These mechanisms simultaneously promote apoptosis and ferroptosis, both as a monotherapy and in combination with venetoclax in leukemia models [42]. Notably, the induction of ferroptosis by bithionol can be mitigated by the ferroptosis inhibitor ferrostatin-1 (Fer-1), further elucidating the mechanism of action and offering insights into potential therapeutic strategies (Figure 2) [42].

4.2 Nanocompounds inducing ferroptosis

Nanotherapy represents an emerging and innovative avenue in addressing complex diseases such as AML. Advanced research has led to the development of intricate nanocomposites capable of modulating intracellular GSH levels and suppressing the activity of GPX4, thereby facilitating ferroptosis and introducing new possibilities for AML treatment [43]. These approaches allow for highly targeted interventions at both cellular and molecular levels, offering significant potential to regulate critical biological pathways. A ferroptosis-inducing nanotherapeutic (GCFN) engineered using a GSH-reactive cysteine polymer has shown significant potential in preclinical models of aggressive AML. GCFN effectively triggered lipid peroxidation and ferroptosis by reducing intracellular GSH levels and suppressing GPX4 activity, highlighting its promise as a novel therapeutic approach for AML [44]. Additionally, gold nanorods (GnR) functionalized with chitosan and a 12-mer peptide (GnRA-CSP12), along with GCFN, have demonstrated the property to activate ferroptosis in AML cells by alternating the equilibrium between GSH and ROS while inhibiting GPX4 synthesis [45]. GNPIPP12MA is a nanocomposite that incorporates an FTO inhibitor and is bioengineered with GSH. Through the FTO/m6A signaling pathway, GNPIPP12MA depletes GSH, resulting in GPX4 inactivation, inhibition of lipid peroxidation (LPO) reduction, elevated intracellular iron accumulation, and selective induction of ferroptosis in AML cells [46]. This nanocomposite demonstrates a wide spectrum of anti-AML effects, even at relatively low doses. Additionally, GNPIPP12MA has the potential to enhance antileukemic immunity by promoting the infiltration of cytotoxic T cells (Figure 2) [46].

4.3 Natural compound activating ferroptosis

The discovery of bioactive compounds from natural sources has played a crucial role in advancing therapeutic options for numerous diseases, including autoimmune inflammatory conditions, neurological disorders, metabolic syndromes, and cancer [47]. Compared to synthetic drugs, these natural molecules often present fewer side effects, making them promising candidates for drug development. Recent investigations have focused on the ability of certain bioactive compounds to activate the ferroptosis pathway in AML cell models [48]. These studies underscore the therapeutic potential of these compounds and their ability to address challenges associated with standard treatments, such as drug resistance and off-target toxicity. Polyphyllin I (PPI), a steroidal saponin isolated from Paris polyphylla, has shown significant therapeutic efficacy in both in vitro and in vivo AML models, including improved survival in xenograft mouse models [49]. PPI operates through a dual mechanism: it suppresses GPX4 expression, compromising the antioxidant defenses of cancer cells, and inhibits the PI3K/mTOR pathway, which is essential for cellular proliferation. Interestingly, PPI demonstrates a stronger ability to induce ferroptosis compared to erastin, positioning it as a potentially superior anti-cancer agent [49]. Honokiol (HNK), derived from species of Magnolia, has emerged as a key modulator of oxidative stress through its regulation of heme oxygenase 1 (HMOX1) [49]. Unlike traditional ferroptosis inducers, HNK activates ferroptosis independently of GPX4, primarily by upregulating HMOX1. The enzymatic activity of HMOX1 increases intracellular iron levels and ROS, culminating in ferroptosis in AML models [50]. This effect is reversed when cells are co-treated with the HMOX1 inhibitor ZnPP, confirming the direct role of HMOX1 in HNK’s mechanism of action. These findings highlight HNK as a therapeutic candidate with a distinct approach to inducing ferroptosis. Licochalcone A (Lico A), a flavonoid derived from the root of Glycyrrhiza glabra, exerts its effects by reducing the expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a protein critical for stabilizing mouse double minute 2 homolog (MDM2) mRNA via m6A modifications [51]. By suppressing IGF2BP3, Lico A enhances the tumor-suppressive activity of p53, leading to increased ferroptosis both in vitro and in vivo (Figure 2) [51]. These findings emphasize the potential of natural compounds as Lico A to modulate epigenetic pathways, offering a novel strategy for ferroptosis-driven cancer therapies.

4.4 Ferroptosis inducers through autophagy regulation

Autophagy, a conserved cellular process involved in the degradation and recycling of intracellular components, plays a critical role in regulating ferroptosis [52]. In the context of AML, autophagy contributes to ferroptosis by facilitating ferritinophagy, a process that liberates intracellular iron and enhances lipid peroxidation [53]. Targeting autophagic pathways offers a unique approach to amplify ferroptosis in AML cells, creating opportunities for innovative therapeutic strategies.

Notably, ATPR, a novel all-trans retinoic acid derivative, induces ferroptosis in AML cells by promoting ROS accumulation that triggers autophagy activation and disrupts iron homeostasis. This cascade leads to AML cell differentiation and growth inhibition, illustrating the therapeutic potential of targeting autophagy-mediated ferroptosis [3]. Similarly, neratinib, a tyrosine kinase inhibitor, has been shown to induce autophagy-dependent ferroptosis; inhibition of autophagy significantly diminishes neratinib’s ferroptosis-inducing effects, further underscoring the essential role of autophagy in mediating ferroptotic cell death in AML [3]. The AMP-activated protein kinase (AMPK)/mTOR pathway plays a critical role in regulating autophagy by maintaining cellular energy homeostasis. Under low-energy conditions, AMPK activation inhibits mTOR, thereby promoting autophagy as a cellular survival mechanism. The antimalarial drug dihydroartemisinin (DHA) and the flavonoid glycoside plant extract Typaneoside (TYP) are closely associated with ferroptosis activation through ferritin degradation mediated by the AMPK/mTOR pathway. This process results in the release of iron, which triggers oxidation reactions and subsequent cellular damage [54, 55]. To support the critical role of autophagy activation in regulating iron homeostasis and ferroptosis, studies conducted in AML cellular models have demonstrated that the use of the autophagy inhibitor 3-methyladenine (3-MA) attenuates lipid peroxidation induced by the tyrosine kinase inhibitor (TKI) neratinib [56]. The disruption of redox homeostasis and ROS balance induced by propionate triggered mitochondrial fission and mitophagy, processes that enhanced both ferroptosis and apoptosis [56]. Additionally, propionate-induced ACSL4-mediated ferroptosis increased the immunogenicity of AML cells, facilitating the release of damage-associated molecular patterns (DAMPs) and promoting the maturation of dendritic cells (DCs) (Figure 2) [57].

4.5 Genetic and epigenetic activation of ferroptosis

Genetic and epigenetic mechanisms regulate ferroptosis, influencing processes such as redox balance, lipid metabolism, and iron homeostasis. Epigenetic modifications, such as changes in histone structure and the activity of noncoding RNAs (ncRNA), add complexity to ferroptosis regulation and offer promising therapeutic targets [58]. Gene knockdown studies have been particularly valuable in uncovering the functions of specific genes regulating ferroptosis. For instance, silencing GPX4 in AML cells induces ferroptosis, characterized by mitochondrial lipid peroxidation, and demonstrates significant anti-leukemic effects both in vitro and in vivo [59]. Recent studies have identified a novel ncRNA, CircKDM4C, which acts as a competitive endogenous RNA for the microRNA (miRNA) hsa-let-7b-5p, enhancing p53 activity and driving ferroptosis [60]. Elevated levels of brain and muscle Arnt-like protein-1 (BMAL1), commonly observed in AML patients, correlate with poorer outcomes. BMAL1 modulates ferroptosis resistance in AML cells via the BMAL1-HMGB1-GPX4 axis, while its depletion sensitizes these cells to first-line chemotherapeutic agents like venetoclax, dasatinib, and sorafenib [61]. Combination therapy involving the histone deacetylase (HDAC) inhibitor CS055 and the peroxisome proliferator-activated receptor (PPAR) pan-agonist chiglitazar has demonstrated selective efficacy against LSCs while sparing healthy hematopoietic progenitors. The non-thiazolidinedione small-molecule chiglitazar enhances the suppression of HDAC3 by CS055, leading to ferroptosis in LSCs through xCT downregulation [62]. This process involves increased H3K27 acetylation at the activating Transcription Factor 3 (ATF3) promoter, upregulating ATF3 expression, which suppresses xCT [62]. Additionally, targeting aldehyde dehydrogenase 3 family member A2 (ALDH3A2) in AML cells enhances the effects of GPX4 inhibitors, inducing ferroptosis without compromising normal hematopoietic cell function. This highlights the potential of combining ALDH3A2 depletion with ferroptosis-inducing strategies as a novel therapeutic approach for AML (Figure 2) [59].

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5. Conclusions

In summary, ferroptosis represents a crucial mechanism of cell death in AML, influenced by a complex network of cellular and metabolic processes. AML cells are particularly vulnerable to ferroptosis cause of their heavy reliance on mitochondrial respiration, increased ROS production, and iron accumulation, all of which contribute to lipid peroxidation. However, these cells also employ various strategies to resist ferroptosis, including the activation of antioxidant pathways such as NRF2 and the modulation of iron homeostasis via the TFR system and ferritin. The intricate interplay between ferritin and FPN, as well as processes like ferritinophagy, further fine-tunes the susceptibility to ferroptosis in AML cells. These adaptive mechanisms suggest that targeting specific points within the ferroptosis pathway, such as lipid metabolism, redox balance, and autophagy, could improve therapeutic outcomes. Combining ferroptosis-inducing strategies with traditional chemotherapy holds promise for overcoming treatment resistance. Additionally, genetic and epigenetic factors that regulate ferroptosis, including GPX4 silencing or ALDH3A2 inhibition, present potential avenues for selective therapeutic interventions. The increasing understanding of ferroptosis regulation in AML provides valuable insights for developing novel treatments that selectively target leukemic cells while minimizing damage to healthy hematopoietic tissues.

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Acknowledgments

We thank D. Mancinelli for English language editing.

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Conflicts of interest

The authors declare no conflict of interest.

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Funding

This work was funded by the National Plan for NRRP Complementary Investments (PNC, established with the decree-law 6 May 2021, n. 59, converted by law n. 101 of 2021) in the call for the funding of research initiatives for technologies and innovative trajectories in the health and care sectors (Directorial Decree n. 931 of 06-06-2022)—project n. PNC0000003—AdvaNced Technologies for Human-centrEd Medicine (project acronym: ANTHEM). This work reflects only the authors’ views and opinions; neither the Ministry for University and Research nor the European Commission can be considered responsible for them (VC). In addition, this work was also funded by MUR-PRIN/PNRR2022:P2022F3YRF (LA); MUR-PRIN/PNRR2022:P20225KJ5L (VC); MUR-PRIN 2022A93K7S (VC); PNRR-MAD-2022-12376723 (LA); and PNRR-MAD-2022-12375755 (VC).

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Written By

Gregorio Favale, Vincenza Capone, Daniela Carannante, Giulia Verrilli, Antonio Beato, Fatima Fayyaz, Rosaria Benedetti, Lucia Altucci and Vincenzo Carafa

Submitted: 21 February 2025 Reviewed: 29 May 2025 Published: 24 June 2025

© The Author(s). Licensee IntechOpen. This content is distributed under the terms of the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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