Potential diagnostic, prognostic, and therapeutic implications of ferroptosis in myelodysplastic syndromes

Abstract

Myelodysplastic syndromes (MDS) are a heterogeneous group of malignant disorders originating from hematopoietic stem cells. Ineffective hematopoiesis, peripheral blood cytopenia, immune disorder, and a high risk of progression to acute myeloid leukemia (AML) are typical characteristics of MDS. The diagnosis and management of MDS is still challenging due to the myriad of other causes of cytopenias and the various clinical presentations of the disease. Moreover, the current therapeutic strategies for MDS have limited efficacy. This emphasizes the importance of exploring novel diagnostic, prognostic, and therapeutic approaches. Ferroptosis is a recently identified distinct form of regulated cell death dependent on iron stores. Iron overload occurs in a considerable percentage of patients with MDS. Many patients with MDS become dependent on blood transfusions and develop transfusional iron overload, which is exacerbated by increased absorption of dietary iron in response to ineffective erythropoiesis. In case of iron overload, the non-transferrin-bound iron in the serum reacts with hydrogen peroxide and generates reactive oxygen species (ROS). Moreover, iron overload can result in a reduction of Glutathione (GSH) levels and decreased activity of Glutathione peroxidase 4 (GPX4), which results in uncontrolled iron-dependent lipid peroxidation and a toxic accumulation of lethal ROS within the cell, which ultimately triggers ferroptosis. Recent studies have identified several ferroptosis-related genes (FRGs) that may serve as biomarkers for diagnosis and prognosis in MDS. Moreover, it has been documented that targeting ferroptosis could be a potential strategy for treating MDS, particularly targeting iron metabolism, GSH/ suppressing system Xc-, and FRGs to induce ferroptosis may provide therapeutic benefits to MDS patients. Therefore, this review summarizes the current knowledge on the diagnostic, prognostic, and therapeutic implications of ferroptosis and its related genes in MDS.

Introduction

Myelodysplastic Syndrome (MDS) is a highly heterogeneous group of clonal hematopoietic disorders originating from hematopoietic stem cells in the bone marrow, characterized by ineffective hematopoiesis, peripheral blood cytopenias, and a risk of progression to acute myeloid leukemia (AML) [1, 2]. Moreover, MDS is the most common acquired bone marrow failure syndrome, which is often accompanied by iron overload [3]. Despite advances in supportive care, MDS carries a highly variable prognosis, with median survival ranging from approximately 9 months in very high-risk cases to over 5 to 8 years in lower-risk patients, with roughly 30% of cases overall progressing to AML [4].

The pathophysiology of MDS is complex, involving genetic mutations in RNA splicing (e.g., SF3B1), epigenetic modifications (e.g., histone modification, DNA methylation), cytogenetic abnormalities, and signaling pathways (e.g., TP53), leading to clonal dominance and apoptosis-prone progenitors [3, 5, 6]. The majority of genetic abnormalities are caused by the loss or acquisition of large fragments of chromosomes, such as -7, 5q-, -5, and + 8 [7].

According to the French–American–British (FAB) classification system, MDS subtypes include refractory anemia (RA), refractory anemia with ring sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-t), and chronic myelomonocytic leukemia (CMML). This morphology-based system was later refined by the World Health Organization (WHO) MDS classification schemes. It incorporates morphologic features such as bone marrow and peripheral blood blast percentage, degree of dysplasia, ring sideroblasts, bone marrow fibrosis, and bone marrow hypocellularity, and also recognize three genetically defined entities: isolated del(5q) cytogenetic abnormality, SF3B1 mutation, and TP53 mutation [8].

Ferroptosis

Ferroptosis is a distinct form of regulated cell death that differs fundamentally from apoptosis, necrosis, and autophagy. It is characterized by the iron-dependent accumulation of lipid peroxides. Mechanistically, ferroptosis arises from a disruption of cellular redox homeostasis, in which the balance between oxidant production and antioxidant defenses is impaired [9–11]. This redox imbalance may result from dysregulated iron metabolism, altered function of iron carriers, and/or defective synthesis or activity of lipophilic antioxidant systems [12, 13]. The process is pathway is governed by a distinct set of genes that regulate iron metabolism, lipid peroxidation, and oxidative stress [3, 14].

Imbalances of iron homeostasis may induce cell death [15]. Iron is a fundamental element for life, playing an essential role in cell metabolism and proliferation. It has also been closely linked to the formation of reactive oxygen species (ROS). Intracellular iron is primarily regulated by the iron-storage protein called ferritin, while extracellular iron first binds to the transport protein transferrin for cellular uptake [12]. The circulating transferrin-iron complex binds to the transferrin receptor1 (TFR1) on the cell surface and is subsequently brought inside through endocytosis [16]. When the binding capacity of transferrin is exceeded, detectable levels of non- transferrin bound iron (NTBI) appear in the plasma. A subfraction of NTBI with the weakest binding to plasma biomolecules is labile plasma iron (LPI), which is redox-active and able to permeate cell membranes and reacts with H₂O₂ (hydrogen peroxide) via the Fenton reaction, a process that generates large amounts of ROS and oxidizes lipids [16, 17]. Ultimately, abnormal iron metabolism results in ferroptosis [18, 19].

The oxidative stress could be exacerbated by the functional loss of key antioxidant regulators. Glutathione peroxidase 4 (GPX4) and cystine/glutamate antiporter (also called system Xc⁻) are among the key antioxidant regulators, particularly in the context of lipid peroxidation and ferroptosis prevention [20]. GPX4 is a crucial regulator of iron-induced mortality in the GPX family. It protects a cell from iron-dependent lipid peroxidation and maintains membrane integrity by detoxifying harmful compounds, like ROS buildup [21, 22]. In doing so, GPX4 maintains intracellular redox balance [23].

Glutathione (GSH) is an essential cofactor for GPX4 in the reduction of lipid peroxides [24]. It is a tripeptide synthesized from cysteine, glutamate, and glycine. Maintenance of the intracellular GSH pool depends on NADPH, which is required for the regeneration of reduced GSH from its oxidized form (GSSG) via glutathione reductase. NADPH is generated predominantly by the pentose phosphate pathway (PPP), which diverts glucose-6-phosphate from glycolysis through the action of glucose-6-phosphate dehydrogenase (G6PD) [24, 25]. Consistently, depletion of GSH impairs GPX4-mediated lipid peroxide detoxification, leading to uncontrolled iron-dependent lipid peroxidation and toxic accumulation of ROS, ultimately triggering ferroptosis [26, 27].

The cystine/glutamate antiporter transport mechanism plays a critical role in preventing ferroptosis by maintaining high intracellular GSH levels [20, 28]. It is responsible for sustaining the intracellular supply of cysteine. It facilitates the uptake of extracellular cystine, oxidized form. Upon entry into the cell, cystine is efficiently converted into cysteine, an amino acid that participates in the synthesis of GSH [29]. The inhibition of cystine/glutamate antiporter indirectly but effectively suppresses GPX4 activity by cutting off the supply of its necessary cofactor. This leads to a severe decline in the cellular antioxidant capacity, the accumulation of lethal ROS, and the accumulation of toxic lipid peroxides on the cell membrane, ultimately triggering oxidative cell death, known as ferroptosis [18, 19]. Overall, dysregulation of the GPX4 and cystine/glutamate antiporter pathways can lead to increased susceptibility to ferroptosis [30, 31].

It has been reported that ferroptosis exhibits a dual role in cancer biology. It primarily acts as a tumor suppressor by inducing iron-dependent lipid peroxidation in malignant cells that are vulnerable due to metabolic dysregulation, such as elevated labile iron levels and GSH depletion [32]. However, in certain contexts, ferroptosis may also promote tumor survival or therapy resistance. Cancer cells can actively acquire ferroptosis resistance by upregulating antioxidant networks and reprogramming lipid metabolism, and insights into these mechanisms may reveal therapeutic vulnerabilities [33]. Sublethal ferroptotic stress can paradoxically promote tumorigenesis by triggering adaptive responses, such as NRF2 activation, which induces antioxidant genes (e.g., SLC7A11 and GPX4), allowing cells to evade complete execution of cell death and survive under oxidative stress [34]. Accordingly, ferroptosis-related pathways may contribute to adaptive resistance and metabolic plasticity in malignant cells [33]. This complexity necessitates cautious interpretation of ferroptosis-induction strategies. The purpose of this review is to summarize the current state of knowledge regarding the role of ferroptosis in MDS, with particular emphasis on its diagnostic, prognostic, and therapeutic potential.

Ferroptosis in the development and progression of MDS

Iron overload in MDS

Iron overload plays an important role in the occurrence and development of MDS [35]. Iron overload in MDS occurs primarily as a result of repeated blood transfusions and ineffective hematopoiesis [36, 37]. Blood transfusions to manage anemia are the main source of progressive iron overload in transfusion-dependent MDS patients. Because maximal daily iron absorption is 4 mg (1.4 g per year), the amount of iron acquired from RBC transfusion exceeds sixfold that gained from gastrointestinal absorption [37].

Iron overload may also occur in MDS patients who do not receive RBC transfusions, due to ineffective erythropoiesis, which stimulates intestinal iron absorption, mediated through the suppression of hepcidin production [38, 39]. Hepcidin is a key hormone involved in iron homeostasis and plays a significant role in the pathogenesis of iron overload in patients with MDS [39]. Under normal physiological conditions, hepcidin downregulates iron absorption in the duodenum by binding to and inducing the degradation of ferroportin, the body’s sole cellular iron exporter. Dysplastic and ineffective erythropoiesis triggers the secretion of specific cytokines by maturing erythroblasts, which in turn suppresses hepatic hepcidin production. Consequently, a deficiency in hepcidin leads to unrestrained intestinal iron absorption, ultimately exacerbating systemic iron overload [15, 39, 40]. Studies suggest that erythropoiesis-mediated hepcidin suppression is proportional to the degree of erythroid expansion [37]. This iron dysregulation not only worsens cytopenias but also heightens susceptibility to regulated cell death modalities like ferroptosis [41].

It has been increasingly thought that iron overload may contribute to MDS progression through the induction of ferroptosis [17]. In case of acute iron overload, the NTBI in the serum reacts with H₂O₂ and generates ROS [16, 17]. Moreover, iron overload can result in a reduction of GSH levels and decreased activity of GPX4, while simultaneously causing an increase in the amount ROS [42, 43]. The idea can be supported by an experiment conducted by Jin et al. [44] who used a RUNX mutant vector combined with iron dextran to induce iron overload in mice and observed inhibition of hematopoiesis accompanied by increased ROS. Overall, the accumulation of free iron drives a toxic process known as lipid peroxidation, which subsequently leads to a distinct form of oxidative cell death called ferroptosis [18, 19].

Ferroptosis-related genes in MDS

Ferroptosis-related genes (FRGs) have emerged as significant contributors to the pathogenesis of various hematological malignancies, including MDS [3, 37]. The GPX4 gene, a central FRG, encodes glutathione peroxidase 4 (GPX4), a key antioxidant enzyme that prevents lipid peroxidation. Dysregulation or reduced activity of GPX4 increases susceptibility to ferroptosis and may contribute to MDS pathogenesis [30, 31]. Similarly, SLC7A11, a component of system xc⁻, indirectly suppresses ferroptosis by promoting GSH synthesis, a critical cofactor for GPX4 [45]. Legrand et al. demonstrated that downregulation of SLC7A11 in MDS cells harboring SF3B1 mutations markedly sensitizes erythroid precursors to ferroptosis [46].

Mutations in SF3B1 implicate aberrant messenger RNA splicing in the pathogenesis of MDS and represent the most frequent genetic alteration in this disease (~ 30% overall and 80–95% in MDS-RS [47, 48]. The pathogenic mechanisms associated with SF3B1 mutations include impaired erythropoiesis, disordered iron metabolism, hyperinflammatory signaling, and R-loop accumulation, all of which contribute to key clinical features of MDS [49]. Emerging evidence indicates that SF3B1-mutant MDS-RS exhibits increased vulnerability to ferroptosis. The SF3B1 mutations lead to aberrant RNA splicing, resulting in mis-splicing and downregulation of key antioxidant regulators such as GPX4 and SLC7A11. This disruption impairs GSH synthesis and enhances lipid peroxidation [46]. Experimental studies further demonstrate that SF3B1 knockdown sensitizes erythroid precursors to erastin through downregulation of SLC7A11, directly linking MDS-RS to ferroptosis-related oxidative cell death pathways [50].

A broader panel of FRGs, including MDM2, RRM2, SREBF1, PTPN6, PARP9, MAP3K11, MDM4, and EZH2, has been implicated in modulating ferroptosis during MDS progression. Chen et al. highlighted the roles of MDM2 and RRM2 in the development of MDS [51]. Moreover, SREBF1 (upregulates peroxidation-prone lipids), PTPN6/SHP1 (loss amplifies JAK/STAT-mediated oxidative stress), PARP9 (depletes GSH/NADPH through DNA damage responses), MAP3K11 (activates p38/JNK-ROS signaling cascades), MDM4 (cooperates with MDM2 to suppress the FSP1 pathway), and EZH2 (epigenetically represses GPX4 and SLC7A11) collectively modulate ferroptosis and may drive MDS progression, often in association with immune microenvironment alterations [52, 53].

Mutations in TP53 further disrupt ferroptosis regulation, in part through altered control of SLC7A11, and are strongly associated with poor prognosis, rapid transformation to AML, and resistance to therapy. Upstream factors such as iron overload (which increases non-transferrin-bound iron and ROS generation) and system xc⁻ activity (which sustains cysteine availability and GSH synthesis) further integrate these ferroptosis-related pathways in MDS [54, 55]. Collectively, these findings underscore the mechanistic and signaling complexity of ferroptosis in MDS pathobiology (Fig. 1) (Table 1).

Fig. 1.

The molecular regulation and related signaling pathways of ferroptosis in MDS

Table 1.

Summary of factors influencing the effect of ferroptosis in the development of MDS

Factors	Ferroptosis mechanism	Role in the development of MDS	References
Iron overload	Increases NTBI, which reacts with H₂O₂ and generates ROS	Promoting oxidative stress and influencing ferroptosis-related pathways	[3]
system Xc⁻	Responsible for sustaining the intracellular supply of cysteine, an amino acid that participates in GSH synthesis	Promotes lipid peroxidation by suppressing GPX4 activity	[18, 19]
GPX4	Encodes enzyme, GPX4, preventing lipid peroxidation; inhibition causes ferroptosis	Dysregulation increases susceptibility to ferroptosis in high-risk MDS	[30, 31]
SLC7A11	Promotes GSH synthesis for GPX4 via system xc⁻; suppression sensitizes to ferroptosis.	Downregulation in SF3B1-mutant MDS enhances erythroid ferroptosis	[46]
MDM2	E3 ligase inhibiting p53; depletion induces GPX4-independent ferroptosis	Associates with immune cell infiltration; drives clonal expansion	[51, 56]
RRM2	Encodes ribonucleotide reductase subunit essential for DNA synthesis; depletion induces GPX4-independent lipid ROS accumulation	RRM2 expression correlates with immune cell infiltration; promotes ineffective hematopoiesis & genomic instability	[51]
SREBF1	Upregulates peroxidation-prone lipid synthesis	Enhances dysplastic lipid metabolism, ferroptosis vulnerability	[52]
PTPN6 (SHP1)	Loss amplifies JAK/STAT oxidative stress, ferroptosis signaling	Contributes to the inflammatory MDS microenvironment	[52]
PARP9	Depletes GSH/NADPH via DNA damage responses	Exacerbates genomic instability and cell death in MDS	[52]
MAP3K11	Activates p38/JNK-ROS ferroptosis cascades	Promotes clonal evolution via stress signaling	[52]
MDM4	Cooperates with MDM2 to suppress the FSP1 antioxidant pathway	Amplifies MDM2-driven ferroptosis sensitivity	[53]
EZH2	Epigenetically represses GPX4/SLC7A11 expression	Silences ferroptosis resistance in MDS stem cells	[52]
SF3B1	Aberrant splicing ↓ABCB7/↑SFXN1 → mitochondrial Fe overload, RS formation; ↓GPX4/SLC7A11	Defines MDS-RS subtype; sensitizes erythroid precursors to ferroptosis	[46, 47]
TP53	Suppresses ferroptosis via SLC7A11 upregulation; mutations impair this	Poor prognosis, AML transformation, therapy resistance	[54, 55]

Diagnostic/prognostic implications of ferroptosis in MDS

The current diagnosis of MDS relies on compiling the results from several different tests. The main diagnostic criteria include the presence of peripheral cytopenia, evidence of dysplasia in the bone marrow morphology examination, and the detection of clonal cytogenetic abnormalities in the blood-forming cells [57, 58]. However, it may be insufficient for accurately diagnosing MDS due to the myriad of other causes of cytopenias [8] and the various clinical presentations of the disease [59]. Consequently, diagnostic discrepancies occur in approximately 12% of patients at initial presentation, affecting therapeutic decision-making [60]. This emphasizes the need to integrate novel diagnostic approaches to improve accuracy and patient management [8].

Diagnostic and prognostic relevance of FRG in MDS

Recent studies have identified several FRGs that may serve as biomarkers for diagnosis and prognosis in MDS. The expression levels of FRGs can be assessed through various techniques, including quantitative reverse transcription polymerase chain reaction (qPCR) and RNA sequencing. Significant differences in the expression of several FRGs between MDS patients and healthy controls have been reported from bioinformatics datasets, reflecting the potential diagnostic relevance of these gene signatures [51].

Chen et al. [51] identified MDM2 and RRM2 as key FRGs for the diagnosis of MDS. Their expression levels were measured in bone marrow samples from patients with MDS and healthy controls using qPCR. The result indicated that both genes showed a significantly decreased expression. The ROC analysis demonstrated that both genes had AUC values greater than 0.78, indicating that they may serve as potential diagnostic biomarkers for MDS with favorable accuracy. In a separate study, Salomao et al. have shown that reduced MDM2 expression is associated with severe disease in MDS patients [56]. Furthermore, a study by Zhu et al. [52] developed a six-FRG signature (SREBF1, PTPN6, PARP9, MAP3K11, MDM4, and EZH2) that was validated using qRT-PCR and demonstrated a potential diagnostic relevance, with AUCs of 0.989 and 0.962 in the training and validation cohorts, respectively.

Prognostic models incorporating FRGs have shown considerable promise in predicting disease progression and outcomes in patients with MDS. Several studies have demonstrated that differentially expressed FRGs could estimate disease prognosis. In a study by Chen et al. [51], a FRG signature consisting of MDM2 and RRM2 was developed and validated across multiple independent datasets, showing a potential predictive role for overall survival. Nomogram analyses further confirmed the prognostic value of this FRG signature, indicating its potential utility in clinical practice for risk stratification. Based on the calculated risk score, MDS patients were classified into high- and low-risk groups with significantly different survival outcomes. The model achieved AUC values of 0.810, 0.827, and 0.786 for 1, 3, and 5-year survival prediction in the training cohort, respectively, demonstrating the potential prognostic relevance of FRG in MDS.

A growing body of evidence indicates that specific genetic alterations play critical roles in the diagnosis and prognostic stratification of MDS. Mutations in SF3B1 are particularly significant and are strongly associated with the MDS subtype characterized by RS, ineffective erythropoiesis, a lower risk of leukemic transformation, and prolonged OS [49, 61]. According to WHO and ICC classifications, the presence of SF3B1 mutations supports the diagnosis of MDS with ring sideroblasts even when RS accounts for as little as 5–14% of erythroid precursors. Clinically, SF3B1-mutated patients demonstrate superior OS (approximately 6–8 years) compared with wild-type cases (2–3 years), independent of IPSS-R risk stratification. Moreover, a variant allele frequency (VAF) > 10% correlates with increased RS burden [48, 62].

Furthermore, the loss of functional TP53 protein by loss of both TP53 alleles is associated with a poor outcome for MDS patients with TP53 mutations, and most of the TP53-mutated MDSs belong to the higher-risk subtypes [63]. In addition, TP53 mutations have been shown as an adverse marker in the prognosis of MDS patients [64] and frequently coincide with del(5q) [5].

Diagnostic and prognostic relevance of iron metabolism markers in MDS

Reports suggested that iron overload affected the survival of MDS patients [35, 40] and markers of iron overload portend a relatively poor prognosis [37]. Iron metabolism parameters, serum ferritin (SF), soluble transferrin receptor (sTFR), and LPI in MDS may reflect a state of primary iron overload driven by chronic blood transfusion and ineffective erythropoiesis, even in the absence of blood transfusions.

It has been reported that SF level at baseline is typically elevated, ranging between 200 and 500 ng/mL in lower-risk MDS patients [65]. Iron overload with SF levels > 1000 ng/mL is associated with poor prognosis and remains an independent predictor of both overall and leukemia-free survival [35, 40]. In transfusion-naïve newly diagnosed MDS patients, those with SF < 500 ng/mL show longer survival than patients with SF > 500 ng/mL [50]. De Swart et al. reported elevated median ferritin levels (> 250 µg/L) at diagnosis in both transfusion-dependent and independent MDS patients, with the highest levels observed in the transfusion-dependent groups [66]. Similarly, Cui et al. demonstrated increased SF levels in MDS patients without prior RBC transfusions, suggesting that iron overload may precede transfusion therapy [39]. In patients undergoing myeloablative hematopoietic stem cell transplantation (HSCT), elevated SF levels were strongly correlated with the cumulative number of RBC units transfused [67]. Chronic SF elevation promotes a systemic pro-oxidant state in which persistent redox-active iron depletes GSH, thereby lowering the threshold for ferroptotic cell death in the hematopoietic microenvironment [68, 69]. Iron overload in MDS is commonly assessed using SF due to its availability and low cost; however, its accuracy declines at high levels, and ferritin is an acute-phase reactant elevated during infection, inflammation, and malignancy [40].

The serum concentration of sTfR reflects the level of TfR1 expression on cellular membranes, particularly on erythroid precursors, and therefore serves as a reliable indicator of erythroid mass and functional iron demand, providing an integrated measure of iron supply relative to erythropoietic activity [70]. Unlike serum ferritin, sTfR levels are largely independent of inflammation and reflect cellular iron requirements rather than total body iron stores, making it a valuable complementary biomarker for assessing iron metabolism in patients with MDS. At diagnosis, sTfR levels are frequently elevated, reflecting an expanded but ineffective erythroid progenitor compartment with impaired incorporation of iron into hemoglobin. This mismatch between iron availability and utilization contributes to iron misdistribution and oxidative stress within the bone marrow microenvironment [71]. Metzgeroth et al. showed that low sTfR levels in MDS are associated with reduced and poorly differentiated erythropoiesis and increased RBC transfusion requirements, highlighting heterogeneity among MDS subtypes [72]. Earlier studies also reported increased sTfR levels in MDS with ring sideroblasts (MDS-RS), with the highest concentrations observed in transfusion-independent patients, supporting marked ineffective erythropoiesis and relative hepcidin suppression, leading to increased iron absorption despite impaired erythroid iron utilization [66, 73].

Another critical diagnostic indicator of iron toxicity is the presence of NTBI and its most reactive component, LPI. These species emerge when transferrin saturation (TSAT) exceeds approximately 70% and act as potent catalysts of the Fenton reaction, directly expanding the intracellular labile iron pool and predisposing hematopoietic stem cells (HSCs) to ferroptosis [68]. In this context, Li et al. reported that patients with MDS exhibit significantly increased TFR mRNA expression in CD33⁺ cells compared with healthy individuals, further supporting heightened cellular iron uptake and ferroptotic vulnerability [74]. Clinically, LPI levels > 0.4 µM have been shown to correlate strongly with iron overload [75]. De Swart et al. demonstrated that LPI is a clinically relevant assay for detecting toxic iron overload and its adverse impact on survival in MDS. Elevated LPI in the presence of TSAT > 80% occurred almost exclusively in patients with MDS-RS and/or those who were transfusion dependent. Importantly, detectable LPI independently predicted worse survival, particularly in transfusion-dependent patients without ring sideroblasts [66]. Collectively, these findings support LPI as a real-time indicator that could reflect systemic iron loading status instantaneously and capture iron toxicity beyond conventional iron indices [76].

Therapeutics in MDS

The main approaches used in the current therapy of MDS include hematopoietic stem cell transplantation HSCT [77], hypomethylating agents [78], and blood transfusion as supportive care [79]. Moreover, immunotherapy [80] and inducing ferroptosis [81] are emerging as promising options for MDS, particularly after hypomethylating agent failure or in higher-risk cases. Below, we highlighted the current therapeutic options for MDS with a particular focus on ferroptosis.

HSCT in MDS

Allogeneic HSCT offers the only potentially curative treatment for patients with MDS, providing long-term survival rates of approximately 30%–70% [77]. However, due to compromised bone marrow function and transfusion dependency, HSCT recipients are particularly vulnerable to iron overload. Accumulating evidence supports the concept that iron chelation therapy may reduce iron-mediated toxicity in the bone marrow and promote hematologic recovery and engraftment in HSCT recipients [82]. Although HSCT remains the sole curative option, its significant toxicity restricts its use primarily to younger and medically fit patients [83, 84], leaving the majority of patients who are typically elderly unable to benefit from transplantation [63]. Moreover, post-transplant relapse and graft-versus-host disease (GVHD) continue to represent major clinical challenges [77].

Hypomethylating agents in MDS

Hypomethylating agents such as azacitidine, decitabine, and lenalidomide are the primary pharmacological approach for MDS [84–86]. Hypomethylating agents incorporate into DNA as cytidine analogs and inhibit DNA methyltransferases, thereby reversing aberrant DNA methylation patterns. This leads to gene re-expression, promotes differentiation of dysplastic hematopoietic cells, and exerts cytotoxic effects at low doses, targeting the epigenetic dysregulation characteristic of MDS [78]. In MDS associated with iron overload, hypomethylating agents such as decitabine have been shown to enhance ROS accumulation, resulting in GSH depletion and inhibition of GPX4, ultimately triggering ferroptosis. Hypomethylating agents exploit ferroptosis-related vulnerabilities, potentially countering ineffective hematopoiesis associated with excess iron [3]. However, a significant number of patients develop drug resistance to demethylation therapy [63], experience disease relapse [87], and demonstrate limited long-term therapeutic benefit [88].

Blood transfusions in MDS

Red blood cell (RBC) transfusions remain a cornerstone of supportive care for lower-risk MDS patients to correct anemia but represent the principal source of iron overload in MDS [66]. With chronic transfusion therapy, patients accumulate excessive iron (approximately 250 mg per RBC unit), leading to systemic and tissue iron overload. This excess iron disrupts iron homeostasis by saturating transferrin, increasing NTBI, and promoting iron deposition in organs such as the liver and spleen, while inappropriately low hepcidin levels fail to limit intestinal iron absorption [41]. Transfusion dependence is associated with adverse clinical outcomes in MDS and predicts reduced overall and leukemia-free survival [65]. Consequently, lower-risk MDS patients, who often require prolonged transfusion support, are particularly susceptible to iron overload and its clinical complications [37]. Malcovati et al. demonstrated that transfusion-dependent MDS patients have significantly shorter survival than non-transfusion-dependent patients, with secondary iron overload contributing substantially to this risk [65]. Consistently, there is a need to explore novel or combination therapeutic approaches [63]. It is hoped that the improved understanding of the biological and molecular mechanisms of MDS would enable the exploration of novel therapeutic approaches [74, 83].

Immunotherapy in MDS

Immunotherapy has gained increasing attention as a therapeutic strategy for MDS due to the central role of immune dysregulation in the pathogenesis of MDS. Patients with MDS exhibit altered innate and adaptive immune responses, including T-cell dysfunction, aberrant cytokine signaling, immune checkpoint upregulation, and impaired immune surveillance, which collectively contribute to ineffective hematopoiesis and disease progression [89]. Therapeutic manipulation of the immune system, through immune checkpoint inhibitors, antigen-targeted antibodies, antibody–drug conjugates, tumor vaccines, and adoptive cell therapies, has shown promise in several clinical trials of hematologic malignancies [90]. Accordingly, immunotherapeutic approaches such as immune checkpoint inhibition, chimeric antigen receptor T-cell (CAR-T) therapy, and vaccine-based strategies have now been explored in patients with MDS [80, 89]. CAR-T cell therapy represents an emerging immunotherapeutic approach in MDS, with preclinical and early-phase clinical studies targeting antigens such as CD123, CD33, and FLT3 to eradicate malignant myeloid clones [91, 92].

Growing evidence suggests that ferroptosis can modulate immune responses relevant to tumorigenesis [93]. Ferroptosis may affect innate immunity by altering the abundance and function of immune cells such as macrophages and neutrophils, while also shaping adaptive immune responses by promoting inflammatory or antigen-specific reactions following the recognition of ferroptotic cells by T and B lymphocytes [94].

Targeting ferroptosis in MDS

Targeting ferroptosis is an emerging potential strategy for anti-tumor therapy [95, 96]. Tumor cells that are resistant to conventional treatments may be more sensitive to this form of death due to imbalances in the lipid peroxidation system. A study by Lv et al. [3] in a xenograft mouse model of fibrosarcoma showed that induction of ferroptosis could inhibit tumor growth and induce the death of MDS cells. Consequently, targeting iron metabolism, depleting GSH/ suppressing system Xc⁻, and modulating other ferroptosis-related pathways may provide therapeutic benefits for patients with MDS [37, 51, 97] (Table 2).

Table 2.

Ferroptosis-modulating pharmacological agents and possible mechanisms in MDS

Ferroptosis modulating agent	Target/mechanism	Clinical status in MDS	References
FeCl2 and (NH4)2Fe(SO4)2	↑Labile iron → ROS↑ via Fenton reaction	Preclinical iron enrichment strategies	​ [12, 97]
RSL3	Direct GPX4 inhibition → lipid peroxide accumulation	Studied in solid tumors; a potential for MDS	[103].
Sorafenib	System Xc⁻/SLC7A11↓ → GSH↓ → lipid ROS↑	FDA-approved (AML/HCC); preclinical MDS synergy	[107, 108].
Artesunate	Mechanisms associated with GPX4 inhibition	Phase I/II clinical trials on colorectal cancer	[104]
JKE-1674	GPX4 inhibitor	Preclinical; synergizes with gemcitabine/cisplatin	[105].
IKE	System xc⁻ inhibition	Preclinical	[106]
IKE + ES-Cu synergy	System xc⁻ inhibition → GSH depletion → GPX4 suppression	Preclinical; IKE + ES-Cu synergy in MDS cells	​ [29]
Erastin	System xc⁻ inhibition → GSH depletion → GPX4 suppression	Preclinical	[100]
Erastin with azacitidine	System xc⁻ inhibition → GSH depletion → GPX4 suppression	Preclinical; Erastin/azacitidine synergy in MDS ​	[74]
Decitabine	GSH↓/GPX4↓; ferroptosis contributor	FDA-approved frontline MDS therapy	[3].
Eprenetapopt (APR-246)	↓NRF2/SLC7A11/GSH → ferroptosis sensitization	FDA fast-track	[111, 112]
MDM2 antagonists (DS-3032b, DS-5272)	↓p53 inhibition→GPX4-independent ferroptosis	Phase I/II + azacitidine in MDS	[113].

Targeting iron metabolism

Elevated levels of intracellular iron could trigger an increased accumulation of intracellular ROS, thereby promoting ferroptosis and rendering tumor cells much more sensitive to ferroptotic cell death [98, 99]. The intracellular iron reacts with hydrogen peroxide inside the cells to generate ROS and initiate ferroptosis [16]. A study in the mouse model showed that the increase in ROS level led by iron overload was related to ferroptosis, suggesting iron overload could induce ferroptosis [3]. Thus, ferroptosis can be promoted to exert antitumor effects by disrupting intracellular iron homeostasis. MDS cells often exhibit altered iron metabolism and may be highly susceptible to the oxidative stress induced by excess labile iron [81]. Specifically, targeting iron-metabolism can disrupt the tight regulation of intracellular iron availability. Recently, studies have developed various strategies to enhance intracellular iron enrichment, resulting in increased sensitivity to ferroptosis [12]. The strategies could target proteins involved in dysregulated iron metabolism or directly increase the intracellular iron [12, 100]. Nanotechnology is mainly used to construct iron-based nanocarriers to deliver iron intracellularly [101]. Intracellular iron overload can be induced by certain exogenous substances that contain iron (such as heme chloride, FeCl2, and (NH4)2Fe(SO4)2), leading to the effective initiation of ferroptosis [12].

Targeting GPX4

Ferroptosis inducers exert their effects on GPX4, either directly or indirectly, via various pathways [12]. Inhibitions of GPX4 and system Xc- are two ferroptosis-triggering mechanisms, given that inhibition of system Xc- indirectly suppresses GPX4. A characteristic ferroptotic death is observed in these cells upon GPX4 knockdown [3]. Direct inhibition of GPX4 triggers ferroptosis in sensitive cells, resulting in the accumulation of lipid peroxides [18, 102]. Pharmacologic compounds such as RSL3 and ML162 directly inhibit GPX4 activity, thereby inducing ferroptosis in various cancer models. These agents have been primarily studied in solid tumors, including head and neck cancers [103]. Phase I and II clinical trials evaluating artesunate in colorectal cancer indicated mechanisms associated with GPX4 inhibition [104]. Furthermore, emerging preclinical data suggest that the GPX4 inhibitor JKE-1674, when combined with gemcitabine and cisplatin, exhibits superior antitumor efficacy and may have potential applicability in hematologic malignancies [105].

Depleting GSH/ suppressing system Xc

Inhibition of system Xc⁻ indirectly suppresses GPX4 activity by limiting the supply of cysteine required for GSH synthesis, thereby reducing the availability of its essential cofactor [18, 19]. Depletion of GSH could be done by inhibiting GSH biosynthesis, restricting the availability of cysteine, or blocking the acquisition of cystine from the extracellular environment by inhibiting System Xc- [55]. It has been reported that MDS patients treated with decitabine lead to accumulation of ROS within the bone marrow cells by depleting GSH, and impairing GPX4-mediated lipid peroxide reduction [3]. However, the degree to which ferroptosis influences the survival and treatment strategy in MDS remains unclear [51].

Erastin, sulfasalazine, and sorafenib are small molecules that induce ferroptosis through this mechanism; inhibition of system Xc⁻ indirectly suppresses GPX4 [18, 19]. Imidazole ketone erastin (IKE), a more stable and potent analog of erastin, similarly promotes ferroptosis via system Xc⁻ inhibition [106]. In MDS and other cancer models, blockade of system Xc⁻ by erastin results in GSH depletion, lipid ROS accumulation, and subsequent ferroptotic cell death [18, 100]. Sorafenib, an FDA-approved multikinase inhibitor for hepatocellular carcinoma and renal cell carcinoma, has also been shown to induce ferroptosis by downregulating SLC7A11, leading to GSH depletion and enhanced lipid peroxidation, although its ferroptotic effects may vary depending on cellular context [107, 108]. In hematologic models, sorafenib has shown potential synergy with hypomethylating agents in preclinical settings. Given the iron-overload–associated oxidative stress characteristic of MDS, this combination may theoretically enhance ferroptotic vulnerability; however, further mechanistic and clinical validation is required.

Targeting FRGs

Targeting FRGs presents a compelling strategy for treating MDS by exploiting the mechanism of ferroptosis [81]. The observed associations between FRGs and infiltrating immune cells in MDS highlight the therapeutic potential of targeting FRGs, including the possibility of inducing immune-related ferroptosis to enhance cancer treatment [109].

The TP53 gene provides instructions for making a protein called tumor protein p53 (or p53), which plays a crucial role in suppressing tumors, as it can halt the growth and dissemination of cancer cells [110]. It is now well recognized that TP53-mutant MDS disease represents a singular entity with poor outcomes necessitating dedicated clinical interventions with the hope of developing and optimizing the first TP53-specific agents [54]. Moreover, Eprenetapopt (APR-246) directly targets mutant TP53 to destabilize it, reducing NRF2/SLC7A11 expression and GSH levels, thereby sensitizing MDS cells to GPX4 dysfunction and inducing ferroptosis [111, 112]. Therefore, targeting Tp53-mediated ferroptosis can be a new approach for MDS therapy and may bring breakthroughs in tumor treatment and provide patients with more effective treatment options.

Chen et al. reported that the risk score derived from FRG expression relates to immune cell infiltration in MDS. They further explored potential therapeutic drugs for MDS by performing molecular docking with differentially expressed FRGs. MDM2 and RRM2 were identified as potential therapeutic targets and docked with small compounds. The study highlighted the top three compounds predicted to bind MDM2 (DB15047, DB07570, and DB07297) and the top three for RRM2 (DB13113, DB07479, and DB07794) [51]. Furthermore, Wei et al. provide proof-of-concept evidence that combining an MDM2 antagonist (DS-3032b or DS-5272) with azacitidine may have therapeutic potential in MDS [113].

Synergistic use of ferroptosis inducers

Ferroptosis induction can function synergistically with existing treatments by enhancing antitumor effects and shows broad clinical prospects. A study by Li et al. highlights potential synergistic use of erastin with azacitidine for MDS treatment [74]. Another study showed that erastin combined with decitabine could further reduce the GSH level and decrease the activity of GPX4 [3]. Furthermore, ferroptosis inducer IKE synergistically enhanced Elesclomol-copper (ES-Cu) mediated cytotoxicity of MDS cells. The combination of ES-Cu and IKE increased the number of dead cells and decreased the number of live cells [29].

Nanotechnologies in ferroptosis induction

Although ferroptosis modulation is a promising therapeutic strategy for MDS, significant challenges remain in its clinical translation, including limitations in drug delivery, systemic toxicity, and the development of resistance mechanisms. Advances in nanotechnology suggest that certain nanomaterials may be more effective than conventional biological agents in inducing ferroptosis [114]. By improving pharmacokinetics and enhancing intracellular iron accumulation, nanocarriers can amplify ROS production and lipid peroxidation, thereby potentiating ferroptotic cell death [115, 116]. Preclinical studies, including folate-modified liposomes and all-trans retinoic acid (ATRA)-loaded nanoformulations in solid tumor models, have demonstrated enhanced ferroptosis induction and antitumor efficacy [117].

Nanotechnology-based platforms could offer targeted and sustained delivery of ferroptosis inducers to malignant hematopoietic cells while minimizing off-target effects within the bone marrow microenvironment. Iron-based nanomaterials particularly underscore this translational potential in hematologic malignancies. Zhu et al. developed an Mn–Zn ferrite (Nano-Iron) nanoreagent that modulates redox homeostasis in chronic myeloid leukemia cells and enhances the sensitivity of K562/ADR cells to adriamycin by inducing ferroptosis, thereby reversing drug [118]. Iron-derived nanoparticles directly release bioavailable iron and promote Fenton chemistry–mediated ROS generation, intensifying lipid peroxidation. Importantly, nanomaterial-induced ferroptosis may help overcome resistance associated with mutations in genes such as TP53 or RAS [114], supporting further investigation of ferroptosis-based nanotherapeutics in MDS.

Conclusions

Ferroptosis and its related genes may have diagnostic and prognostic value and could offer potential therapeutic avenues in MDS. This summarized review provides ideas and resources for future research on targeted therapies for MDS, with the potential to improve patient management and outcomes. Notably, further research is needed to validate these results and to fully explore the therapeutic potential of targeting ferroptosis in MDS.

Abbreviations

AML

Acute myeloid leukemia

CMML

Chronic myelomonocytic leukemia

FRG

Ferroptosis-related gene

G6PD

Glucose-6-phosphate dehydrogenase

GPX4

Glutathione peroxidase 4

GSH

Glutathione

GVHD

Graft-versus-host disease

HSCT

Hematopoietic stem cell transplantation

LPI

Labile plasma iron

MDS

Myelodysplastic syndrome

NDDSs

Ferroptosis-based nanodrug delivery systems

PPP

Pentose phosphate pathway

RA

Refractory anemia

RAEB

Refractory anemia with excess blasts

RAEB-t

Refractory anemia with excess blasts in transformation

RARS

Refractory anemia with ring sideroblasts

RBC

Red blood cell

ROS

Reactive oxygen species

SF

Serum ferritin

sTFR

Serum transferrin receptor

TFR

Transferrin receptor

WHO

World Health Organization

WPSS

Prognostic scoring system

Author contributions

MW conceived the concept for this review. All authors involved in the literature searching, designing, writing – original draft, writing – review & editing. All authors approved the final manuscript.

Funding

There was no funding source for this study.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.