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 (
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.
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
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
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
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
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
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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