1. Introduction

1.1 Background and significance of ferroptosis in cancer

Cancer remains a leading cause of mortality worldwide, and despite decades of research and advances in treatment modalities, the struggle against the disease persists^[1]. Current therapies, though beneficial, are frequently limited by issues such as primary and secondary drug resistance and severe side effects associated with the inability to selectively target malignant cells^[2]. In this context, the exploration of alternative cell death mechanisms, such as ferroptosis, has emerged as a promising new frontier in cancer treatment. Ferroptosis is defined by the excessive formation of lipid peroxides on cellular membrane phospholipids, resulting from the failure of the cell’s antioxidant machinery, primarily the glutathione-dependent systems, and dysregulated iron metabolism. Polyunsaturated fatty acids (PUFAs) play a pivotal role in this process, as their incorporation into membrane phospholipids makes them especially susceptible to peroxidation, thereby promoting the execution of ferroptotic cell death. Consequently, several intermediates of the mevalonate and cholesterol biosynthesis pathways, including squalene and 7-dehydrocholesterol (7-DHC), are linked to tumorigenesis and ferroptosis regulation^[3-5]. Further, enzymes such as Acyl-CoA synthetase long-chain family member 4 (ACSL4) and lysophosphatidylcholine acyltransferase 3 (LPCAT3) promote ferroptosis sensitivity by facilitating the incorporation of PUFAs into membrane phospholipids^[6]. In contrast, activation of enzymes that generate monounsaturated fatty acids (MUFAs), such as stearoyl-CoA desaturase-1 (SCD1), confers resistance to ferroptosis^[7,8]. Collectively, pharmacological modulation of the metabolic and lipid remodeling pathways that govern ferroptosis offers a promising strategy to overcome therapy resistance and enhance the selective elimination of cancer cells.

1.2 Historical overview and milestones in ferroptosis research

Given its emerging importance in cancer biology, understanding how ferroptosis was discovered and how the field has evolved over time provides valuable context. Ferroptosis was formally defined in 2012 by Dixon and colleagues^[9]; however, several earlier observations had already delineated this distinct, non-apoptotic form of cell death and its therapeutic potential in cancer. Early studies identified small molecules such as Erastin and RAS synthetic lethal compound 3 (RSL3) that induce a previously unrecognized form of cell death characterized by iron dependence and non-apoptotic mechanisms^[10,11] (Figure 1). Later studies elucidated the central regulatory architecture of ferroptosis, namely those mediated by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). More recent work has revealed lineage-specific vulnerabilities, epigenetic regulators, and microenvironment-dependent mechanisms. This review will first delve into the core mechanisms of ferroptosis, followed by its role in specific cancer types and emerging therapeutic strategies, and will conclude with a discussion of current challenges and future perspectives.

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Figure 1. The evolution of ferroptosis research and its major milestones from discovery to treatment strategies (2003-now). The timeline is divided into 2 eras: 1^st era: Discovery Era (2003-2011): Beginning with the characterization of mammalian selenoproteomes, identification of erastin as an inducer of non-apoptotic cell death in RAS-mutated tumor cells in 2003^[10], and identification of RSL3 as an inducer of cell death in 2008^[11]. 2^nd era: Definition & Mechanism Era (2012-now): Marked by the official introduction of the term “Ferroptosis” by Scott Dixon and colleagues in 2012^[9], they also reported sorafenib inhibits system Xc^- and induces ferroptosis^[138] in 2014. In 2015, the role of p53 in enhancing ferroptosis sensitivity was identified^[198]. Subsequent milestones include: the discovery that radiation can trigger ferroptosis^[134], T cell-mediated anti-tumor activity involves ferroptosis^[133], the discovery of (ferroptosis suppressor protein) FSP1 as a glutathione-independent inhibitor in 2019^[18], and the finding that MYCN-amplified cells are ferroptosis sensitive in 2022^[56]. EMT was found to increase cellular susceptibility to ferroptosis via ZEB1, which enhances lipid peroxidation in 2024^[62]. The discovery that ferroptosis can spread to neighboring cells through membrane contact signaling in 2025^[199]. Created in BioRender. Trumpp, A. (2026) https://BioRender.com/eup5h9n. RSL3: RAS synthetic lethal compound 3; FSP1: ferroptosis suppressor protein 1; EMT: epithelial-to-mesenchymal transition; ZEB1: zinc finger E-box binding homeobox 1.

2. Mechanisms of Ferroptosis

2.1 Core regulatory axes of ferroptosis

Despite over a decade of research into ferroptosis and the identification of numerous regulatory enzymes, the system Xc^-–GPX4 axis remains the central pathway controlling this form of cell death. This axis comprises the cystine/glutamate antiporter (system Xc^-), which imports cystine that is partially used for glutathione (GSH) synthesis, and GPX4, which subsequently utilizes GSH to reduce lipid hydroperoxides, thereby preventing ferroptotic cell death. GPX4 is one of 25 selenoproteins in the human selenoproteome and contains the amino acid selenocysteine (Sec), which is essential for its enzymatic function^[12]. Selenium, an essential trace element, is required for the synthesis of selenocysteine, the 21^st amino acid, through an elaborate, multistep biosynthetic process^[13]. In the liver, selenium is further metabolized and incorporated into selenoprotein P (SELENOP), a Sec-rich protein^[14]. SELENOP is then secreted into the bloodstream and taken up by cells primarily via the LRP8 receptor, serving as the main source of Sec for peripheral tissues. In addition, the system Xc^- has been shown to mediate the uptake of inorganic selenium, thereby promoting selenocysteine biosynthesis and facilitating the production of selenoproteins such as GPX4^[15]. Combining GPX4 inhibitors with conventional treatments, including chemotherapy, radiation therapy (RT), immunotherapy, or targeted therapies, is therefore proposed as a novel strategy to overcome drug resistance in various preclinical models^[16].

Other important ferroptosis-regulatory pathways that function in parallel with GPX4 include FSP1 and GTP cyclohydrolase-1 (GCH1), which operate via selenocysteine-independent mechanisms^[17-19]. In the case of FSP1, it exerts its protective effect by regenerating reduced coenzyme Q10 (CoQ10, or ubiquinol) at the plasma membrane. Ubiquinol, the reduced form of CoQ10, acts as a potent antioxidant by neutralizing lipid peroxyl radicals, thereby inhibiting lipid peroxidation. FSP1 facilitates this process by utilizing NAD(P)H as a reducing agent to regenerate CoQ10. Notably, FSP1 overexpression can partially compensate for GPX4 inhibition, thereby protecting cells from ferroptosis^[20]. Conversely, cancer cells with low FSP1 expression, or those in which FSP1 is epigenetically silenced as observed in leukemia, become reliant on GPX4 for survival^[17]. Recent data indicate that the FSP1-driven ferroptosis defense system is closely linked to vitamin B2 (riboflavin) metabolism, consistent with FSP1 belonging to the flavoprotein family, revealing a key metabolic vulnerability in cancer cells. Unlike classical radical-trapping antioxidants, riboflavin supports FSP1 stability. Mechanistically, FSP1 stability depends on its cofactor flavin adenine dinucleotide (FAD), which is synthesized from riboflavin by riboflavin kinase (RFK) and FAD synthase (FLAD1)^[21]. Importantly, in vivo studies further reveal the context-dependent and therapeutically relevant function of FSP1. In lung adenocarcinoma mouse models, loss of FSP1 increases lipid peroxidation and suppresses tumorigenesis, indicating ferroptosis sensitivity. FSP1 is required for ferroptosis protection in vivo but not in vitro, with its loss causing lipid peroxide accumulation and restored tumour growth upon ferroptosis inhibition^[22]. In metastatic melanoma, oxygen-dependent degradation of GPX4 shifts tumor reliance toward FSP1, which accumulates in a perinuclear pattern and localizes to lysosomes. Inhibition of FSP1 suppresses tumor growth in vivo, whereas in vitro models fail to recapitulate this dependency, underscoring the importance of the tumor microenvironment (TME)^[23]. Complementing the FSP1 pathway, GCH1 represents an additional, independent ferroptosis-suppressive mechanism. GCH1 regulates the biosynthesis and availability of tetrahydrobiopterin (BH4), a potent radical-trapping antioxidant^[19]. BH4 plays a critical role in protecting membrane lipids from peroxidation, supporting the maintenance of ubiquinol levels, and thereby enhancing cellular resistance to ferroptosis. Upregulation of GCH1 expression confers resistance to ferroptosis in colorectal cancer, positioning GCH1 as a potential therapeutic target^[24].

In addition to parallel antioxidant pathways, iron availability can influence sensitivity to GPX4 inhibition. Sodium aurothiomalate (ATM), a clinically approved gold compound, has recently been shown to directly inhibit GPX4 and induce ferroptosis, with its efficacy significantly enhanced by ferric ammonium citrate (FAC). In preclinical models of acute myeloid leukemia (AML) and neuroblastoma, this combination enhances the cytotoxicity of ATM and overcomes the limited efficacy of GPX4 inhibition alone. The combined administration of ATM and FAC exerts a synergistic antitumor effect, resulting in marked tumor growth reduction. These findings highlight iron-dependent oxidative stress as an important determinant of ferroptosis sensitivity^[25], as discussed further in the subsequent section.

2.2 Iron metabolism: A controversial but strategic therapeutic target

Iron plays a complex role in ferroptosis by promoting cell death and serving as a potential therapeutic target, yet the precise mechanisms underlying this process remain under investigation. Maintaining cellular iron homeostasis and tightly regulating labile iron pools is critical for preserving cellular integrity. Thus, elevated levels of free iron primarily induce macromolecular damage via the Fenton reaction, which generates highly reactive hydroxyl radicals (•OH), though whether iron plays a role beyond this mechanism remains to be elucidated^[26]. Recent studies highlight iron supplementation as a strategy to enhance ferroptosis sensitivity by increasing intracellular labile iron and reactive oxygen species (ROS) in a context-dependent manner. For instance, in ovarian cancer models, Fe³⁺ exposure elicits distinct responses between HEY cells and PEO1 cells. During spheroid formation, both HEY cells and PEO1 cells adapt by upregulating ferritin heavy chain 1 (FTH1) and reducing the labile iron pool (LIP) and ROS; however, PEO1 cells exhibit a more pronounced capacity to buffer iron through coordinated upregulation of CD71 and iron storage, thereby maintaining ferroptosis resistance under iron-rich conditions, whereas HEY cells display limited buffering capacity and remain susceptible to iron-induced lipid peroxidation and ferroptosis^[27].

The role of iron in ferroptosis is controversial, in part owing to its dual nature as both an essential micronutrient and a potent pro-oxidant. This duality presents significant challenges and opportunities in cancer therapy. On one hand, iron is indispensable for numerous biological processes, including DNA synthesis, oxygen transport, and energy metabolism. Rapidly proliferating cancer cells often exhibit an increased demand for iron, leading to an “iron addiction” that can be exploited therapeutically. As discussed, increasing the labile iron pool can drive ferroptosis by fueling the Fenton reaction and promoting lipid peroxidation^[28,29]. Strategies like iron supplementation or the use of iron-loaded nanoparticles aim to leverage this pro-ferroptotic aspect of iron to selectively eliminate cancer cells. On the other hand, uncontrolled iron accumulation and subsequent ferroptosis can lead to systemic toxicity, particularly in vital organs with high iron turnover or lipid metabolism, such as the liver, heart, and brain. This narrow therapeutic window necessitates precise targeting strategies to ensure ferroptosis induction is confined to tumor cells while sparing healthy tissues. Furthermore, some cancer cells can adapt to high iron levels by upregulating iron efflux mechanisms or enhancing antioxidant defenses, leading to resistance^[29].

The controversy extends to clinical applications: while iron chelation has been explored to inhibit ferroptosis in certain non-cancerous pathologies, in cancer the goal is often to induce ferroptosis. This requires a precise amount of iron, enough to trigger ferroptosis in tumor cells without causing detrimental systemic iron overload or off-target effects. The development of tumor-specific iron delivery systems and robust biomarkers to monitor intracellular iron levels and ferroptosis induction in real-time are crucial for navigating this therapeutic tightrope. Thus, iron remains a fascinating yet challenging target, demanding a nuanced understanding of its complex biology for safe and effective clinical translation. In particular, the use of iron chelators, which typically inhibit ferroptosis, adds further complexity in combination therapies across different malignancies, as discussed below (Figure 2).

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Figure 2. Overview of iron homeostasis pathways regulating ferroptosis and apoptosis in cancer. Neratinib increases the expression of TFR1, enhancing iron uptake, while salinomycin promote the degradation of ferritin, leading to elevated free iron levels. Artemisinin induces ferritinophagy, a selective form of autophagy that targets ferritin for lysosomal degradation, and the presence of CD44 receptors, often upregulated in cancer stem cells, further contributes to intracellular iron accumulation, promoting ferroptosis. In contrast, iron deficiency induced by iron chelators and gallium can trigger apoptosis by limiting the availability of iron necessary for critical DNA repair and replication processes. This dual nature of iron homeostasis highlights its critical role in determining cell death modalities and highlights the potential for targeted interventions to exploit these pathways for therapeutic benefit. Additionally, hepcidin, a central regulator of cellular iron efflux by controlling the abundance of the iron exporter ferroportin, represents a valuable indicator of intracellular iron levels. Created in BioRender. Trumpp, A. (2026) https://BioRender.com/eup5h9n. TFR1: transferrin receptor 1; DFX: deferasirox; DFO: desferrioxamine; ROS: reactive oxygen species; HMOX1: heme oxygenase 1.

2.2.1 Combination therapies with desferrioxamine (DFO)

Several earlier studies investigated iron chelators in combination therapies before ferroptosis was formally identified. For example, Kim et al. showed that combining RT with the iron chelator DFO did not enhance cytotoxicity compared to radiation alone but enhanced radiosensitization by impairing the repair of radiation-induced DNA damage, highlighting a complex interaction between iron modulation and RT^[30]. In high-risk neuroblastoma, the D-CECaT protocol (cyclophosphamide, etoposide, carboplatin, thiotepa, and deferoxamine) yielded promising outcomes, with 50 of 57 patients achieving complete to partial responses. Here, DFO is thought to act by chelating intracellular iron, thereby inhibiting ribonucleotide reductase and other iron-dependent enzymes, leading to impaired DNA synthesis and repair. However, severe adverse effects, including acute blindness and pulmonary syndrome, were observed, underscoring the narrow balance between efficacy and toxicity when targeting iron metabolism^[31-33]. In ovarian cancer, high expression of ferritin light chain (FTL), divalent metal transporter 1 (DMT1), and Hepcidin correlates with poor prognosis. Notably, combining cisplatin with DFO enhanced therapeutic efficacy by promoting apoptosis and reducing the cancer stem cell population. This result was accompanied by downregulation of p53 and BCL-2 and upregulation of pro-apoptotic markers such as BAX and caspase-8^[34].

In pancreatic cancer, Lang et al. combined DFO with lificiguat (YC-1), a hypoxia-inducible factor-1 (HIF-1) inhibitor, to counteract DFO-induced HIF-1 upregulation that promotes angiogenesis and tumor growth. Co-delivery via a TFR-1-targeting liposome produced synergistic effects in cell lines and xenograft models^[35]. In esophageal cancer, Ford et al. showed that iron chelators (DFO or deferasirox (DFX)) enhanced the efficacy of standard chemotherapeutics (cisplatin, fluorouracil and epirubicin) in both in vitro and in vivo models, notably reducing viability in cisplatin-resistant TE-4 cells^[36]. In triple-negative breast cancer (TNBC), Tury et al. reported that combining DFX with doxorubicin (DOX) improved disease-free survival and delayed recurrence in patient-derived xenografts without increasing toxicity, likely through downregulation of phosphatidylinositol 3 kinase (PI3K) and nuclear factor kappa B (NF-κB) pathways^[37]. Thus, although DFO may compromise the efficacy of certain treatments, it holds promise in combination with chemotherapy in specific contexts, yet its clinical use must be approached with caution given the potential for adverse effects and drug interactions.

2.2.2 Combination therapies with triapine

3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine), a thiosemicarbazone iron chelator, inhibits iron-dependent enzymes such as ribonucleotide reductase (RR). Notably, it can also enhance DNA damage and apoptosis by promoting ROS generation through redox-active iron complex formation, thereby enhancing iron dependent oxidative stress, which contributes to lipid peroxidation and ferroptosis under permissive cellular conditions^[38]. In hepatocarcinoma xenograft models, combining triapine with the photosensitizer Ce6 enhanced ROS generation and anti-tumor activity by inducing both apoptosis and ferroptosis^[39]. In non-small cell lung cancer (NSCLC), triapine combined with gemcitabine showed preclinical promise^[40]; however, phase I/II trials were unsuccessful, with no complete or partial responses and high rates of infusion reactions and hematologic toxicity, potentially due to resistance linked to ribonucleotide reductase regulatory subunit M1 and M2 (RRM1/RRM2) expression. As these studies did not consider ferroptosis, re-evaluating them in the context of current insights into iron metabolism may be valuable^[41-43].

In hematological malignancies such as acute AML, acute lymphoblastic leukemia (ALL), high-risk myelodysplastic syndrome (MDS), and chronic myelomonocytic leukemia (CMML), the combination of triapine and cytarabine has shown significant cytotoxic activity, although these effects were originally reported prior to the recognition of ferroptosis as a mechanism of cancer cell death^[44]. An early clinical trial with 32 patients reported four complete remissions and three cases of disease stabilization^[44]. Current insights into ferroptosis present an opportunity to further refine this combination and improve its therapeutic efficacy. In gynecologic cancers, triapine in combination with cisplatin, especially when administered with radiotherapy, has shown promising results by enhancing radiation sensitivity through the inhibition of DNA damage repair^[45,46]. A phase I trial in advanced solid tumors demonstrated that the combination of Triapine with cisplatin is safe, with five of ten patients achieving a stable disease state and oral Triapine showing 88% bioavailability^[47]. A pilot phase II study reported improved metabolic complete response (mCR) rates and increased 3-year progression-free survival in cervical and vaginal cancers without added toxicity. A phase III trial is currently ongoing to confirm these findings^[48]. However, the contribution of ferroptosis to these clinical outcomes remains undefined. Recent advances in iron-targeting strategies have led to the development of dual iron chelators such as the deferasirox-triapine conjugate (DefNEtTrp). These agents combine high-affinity iron binding with the formation of redox-active iron complexes, thereby inhibiting ribonucleotide reductase and inducing both apoptosis and ferroptosis through iron-dependent oxidative stress^[49]. Accordingly, triapine represents a promising anticancer agent, and its efficacy in specific combinations underscores the need for further research to better elucidate and leverage ferroptosis-driven mechanisms.

2.3 Combination therapies with neratinib

Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, exhibits potent anti-tumor activity in human epidermal growth factor receptor type II (HER2)-positive breast cancer^[50]. Notably, it demonstrates significantly greater efficacy against cancer stem cells than salinomycin and further modulates the epithelial-mesenchymal transition (EMT) process via epigenetic mechanisms^[51]. Salinomycin also promotes ferroptosis by indirectly disrupting GPX4 function through the NF-κB/MUC1-C pathway, where it represses both NF-κB and MUC1-C expression, suggesting its potential for use in combination therapies to enhance cytotoxicity against cancer stem cells^[52]. Thiostrepton (TST) is another antibiotic that induces ferroptosis by inhibiting STAT3-mediated GPX4 expression in pancreatic cancer cells, resulting in iron overload, ROS accumulation, and glutathione depletion. These findings suggest that TST could be used in combination cancer therapies by targeting the STAT3/GPX4 pathway to trigger ferroptosis, offering a novel approach for treating resistant cancers^[53].

In summary, iron acts as both an essential micronutrient and a potent pro-oxidant. Excess labile iron fuels ROS generation and drives lipid peroxidation, thereby potentially sensitizing cells to ferroptosis induction. Thus, cancer cells’ ‘iron addiction’ may create a therapeutic vulnerability that can be exploited through iron supplementation, iron-based nanoparticles, or modulation of iron-handling proteins. Conversely, iron chelators such as DFO and triapine can enhance chemotherapy or radiotherapy in specific contexts, although their effects are highly context-dependent. Targeted ferroptosis inducers, including neratinib, salinomycin, dehydroascorbic acid (DHAA), thiostrepton, and BECN1 modulators, synergize with iron modulation to selectively eliminate tumor cells in vitro, in vivo, and in clinical settings. The intricate interplay of the GPX4-System Xc^-, FSP1-CoQ10, and GCH1-BH4 axes, alongside the critical role of iron metabolism, collectively dictates the susceptibility of cells to ferroptosis. These pathways are intrinsically interconnected, forming a complex regulatory network that responds to cellular stress, metabolic cues, and microenvironmental signals. A comprehensive understanding of these interdependent mechanisms is essential for identifying novel therapeutic targets and developing strategies to selectively induce ferroptosis in cancer cells while sparing healthy tissues.

3. Ferroptosis in Specific Cancer Types and Therapeutic Strategies

3.1 Cancer-specific ferroptosis vulnerabilities

Over the past decade, significant progress has been made in understanding ferroptosis and its role in cancer biology. Several processes in tumorigenesis, such as metastasis, therapy resistance, and cancer stem cell maintenance, are influenced by ferroptosis-regulatory pathways. Rapidly proliferating cancer cells are particularly vulnerable due to their reliance on enzymatic and non-enzymatic systems to counteract phospholipid peroxidation, presenting a therapeutic opportunity. Various cancers, including pancreatic cancer^[54], melanoma^[55], or TNBCs^[6], as well as MYCN-amplified neuroblastoma, show selective sensitivity to ferroptosis^[56-58]. Cancer cells exhibit altered lipid biosynthesis and a reliance on antioxidant defenses, characteristics that render them selectively vulnerable to ferroptosis. These mechanistic insights underpin broad ferroptosis-targeting strategies; for example, drug-tolerant persister (DTP) cells, which drive tumor relapse and resist conventional therapies, exhibit heightened reliance on redox regulation and GPX4 for survival^[59-61].

Recently, it has also been shown that during EMT, a critical step in cancer cell metastasis, cells acquire higher levels of PUFA in their membranes. This increased ratio of PUFA is associated with enhanced cellular plasticity, thereby supporting metastatic potential. Key EMT regulators, such as Zinc finger E-box binding homeobox 1 (ZEB1), upregulate the expression of lipid metabolism enzymes including stearoyl-CoA desaturase (SCD), fatty acid synthase (FASN), and ACSL4. While this metabolic reprogramming supports cancer cell plasticity, metastatic capacity, and resistance to therapy, it also promotes the incorporation of PUFAs into cellular membranes, thereby increasing the susceptibility of these cells to ferroptosis^[62] (Figure 3). Notably, inhibiting SCD while administering ferroptosis inducers has been shown to amplify cytotoxicity in cancer cells overexpressing ZEB1 in vivo^[62]. Additionally, ZEB1 modulates lipid metabolism by inducing PPARγ expression^[63] and suppressing GPX4, leading to ferroptosis sensitivity. Moreover, transforming growth factor-beta (TGF-β1), a known inducer of EMT, downregulates the expression of system Xc^- subunits via SMAD3 signaling, resulting in elevated lipid peroxidation and enhancing susceptibility to ferroptosis^[64].

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Figure 3. Relationships among pathways and factors inducing or inhibiting lipid peroxidation. This figure illustrates the interconnections among various pathways and factors that influence lipid peroxidation and ferroptosis susceptibility. CSCs are highlighted for their higher expression of CD44, which leads to iron overload and heightened susceptibility to ferroptosis. The EMT is depicted as being associated with therapeutic resistance and metastasis; however, EMT can also sensitize cells to ferroptosis through several mechanisms. Additionally, the interplay between hypoxia and oxidative stress is represented emphasizing their collective contributions to the regulation of ferroptosis. Overall, these elements suggest a multifactorial regulatory network that governs the susceptibility of cancer cells to ferroptosis, underscoring the complexity of the mechanisms involved. Created in BioRender. Trumpp, A. (2026) https://BioRender.com/eup5h9n. CSCs: cancer stem cells; EMT: epithelial-to-mesenchymal transition; ROS: reactive oxygen species; SCD: stearoyl-CoA desaturase; ACSL4: Acyl-CoA synthetase long-chain family member 4; HIF: hypoxia-inducible factors.

Lipid metabolism lies at the core of ferroptosis, and its dysregulation therefore represents a promising strategy to enhance the efficacy of ferroptosis-inducing cancer therapies. For example, combining the GPX4 inhibitor RSL3 with fatty acid amide hydrolase (FAAH) inhibitors like URB597 slows tumor growth, arrests the cell cycle, and improves survival in xenograft models^[65]. Membrane-bound O-acyltransferases (MBOAT1/2), upregulated by sex hormones, reduce PUFA content and confer ferroptosis resistance in estrogen receptor positive (ER⁺) breast and androgen receptor positive (AR⁺) prostate cancer cells; combining hormone receptor antagonists with ferroptosis inducers like RSL3 enhances cancer cell death^[66]. Dietary PUFAs also suppress tumor progression in pancreatic cancer models^[67]. In prostate cancer, ACSL4 is elevated, particularly in castration-resistant disease, where it promotes fatty acid metabolism, tumor growth, invasion, and resistance to hormone therapy via protein kinase B (PKB/AKT), lysine-specific demethylase 1 (LSD1), and β-catenin signaling. These findings position ACSL4 as both a biomarker and therapeutic target^[68]. Similarly, targeting SCD1 in lung cancer increases ferroptosis susceptibility and enhances immunotherapy efficacy, while blocking cannabinoid receptor 1 (CB1) with rimonabant triggers ferroptosis by downregulating SCD1 and fatty acid desaturase 2 (FADS2) through PI3K-AKT and mitogen-activated protein kinase (MAPK) pathways^[69,70]. Statins also modulate ferroptosis in cancer, for example, simvastatin induces ferroptosis in gastric cancer by suppressing interleukin enhancer-binding factor 3 (ILF3) via reduced H3K14 acetylation, decreasing programmed death-ligand 1 (PD-L1) expression through the DEP domain-containing mTOR-interacting protein (DEPTOR/mTOR) axis, and enhancing CD8⁺T cell cytotoxicity^[71]. Conversely, atorvastatin can trigger ferroptotic death in cardiomyocytes and skeletal muscle by disrupting mitochondrial redox homeostasis through the NRF2 signaling pathway, GPX4, and xCT downregulation^[72]. These findings highlight lipid metabolism as a key vulnerability in cancer and suggest that ferroptosis modulation, combined with targeted therapies, immunotherapy, or dietary interventions, offers a versatile approach while cautioning for potential off-target toxicities.

Moreover, HIFs play opposing roles in ferroptosis. In hypoxic tumor regions, HIF-1α inhibits ferroptosis by upregulating SLC1A1, an important glutamate transporter, and promotes cystine uptake, thereby conferring ferroptosis resistance^[73]. Conversely, HIF-2α promotes ferroptosis (Figure 3)^[74]. Yang et al. demonstrated that cardiac glycosides like digoxin inhibit HIF-1α and reduce GSH, sensitizing colon and renal cancer cells to sulfasalazine, a compound that triggers ferroptosis through system Xc^- blockade^[73]. These findings highlight HIF isoforms as key regulators of redox balance and suggest that combining HIF-1α inhibitors with ferroptosis inducers could effectively target hypoxic tumors.

3.2 Predictive biomarkers and clinical translation challenges

Identifying predictive biomarkers is essential for the optimization of ferroptosis-based treatments. To date, however, no validated biomarkers have been established to be used in the context of ferroptosis, owing largely to the heterogeneity of cancer types and their variable reliance on this pathway. Nevertheless, as discussed above, certain key ferroptosis regulators, such as ACSL4, may to some extent serve as predictive biomarkers. High ACSL4 expression correlates with increased ferroptosis sensitivity by promoting the incorporation of PUFA into membrane phospholipids, as demonstrated in several cancer types^[75]. Moreover, FSP1 and SLC7A11 serve as markers of ferroptosis resistance, reflecting alternative antioxidant defenses^[76]. Mesenchymal cells, particularly CSCs, express high levels of CD44, which mediates endocytosis of iron-bound hyaluronates, increasing intracellular iron and enhancing ferroptosis susceptibility^[77-79]. This role of CD44 has been observed across multiple cancers, including pancreatic, breast, prostate, and colorectal cancers, where elevated iron further sensitizes these cells to ferroptosis^[80], highlighting its potential as both a predictive biomarker and therapeutic target. Despite the therapeutic promise, several clinical translation challenges must be addressed. These include the lack of standardized assays for measuring lipid peroxidation and ferroptosis markers in patient samples, which hinders patient stratification and treatment monitoring. The potential for off-target toxicity in non-cancerous tissues, particularly in organs with high iron turnover or lipid metabolism (e.g., liver, kidney, brain), remains a concern. Furthermore, the development of stable, bioavailable, and tumor-specific ferroptosis-inducing agents is essential to maximize efficacy while minimizing systemic side effects^[81]. Overcoming these challenges will require interdisciplinary efforts, including advanced drug delivery systems and comprehensive biomarker validation.

3.3 Catalytic therapies and ferroptosis induction

Emerging catalytic therapies offer innovative approaches to induce ferroptosis through the in-situ generation of ROS, enabling precise spatial and temporal control over their cytotoxic activity. These modalities operate through external activation of photosensitizers, sonosensitizers, or metal-based catalysts within the TME^[82]. Photodynamic therapy (PDT) utilizes photosensitizers that, upon activation by specific wavelengths of light, generate singlet oxygen (¹O₂) and other ROS. These events have been demonstrated to induce lipid peroxidation and subsequently ferroptosis. Recent studies highlight that PDT can synergistically trigger ferroptosis by depleting GSH or directly causing lipid peroxidation, especially when combined with GPX4 inhibitors^[83]. Complementing this, sonodynamic therapy (SDT) utilizes low-intensity ultrasound and sonosensitizers to generate ROS through acoustic cavitation and sonochemical reactions. SDT has shown promise in inducing ferroptosis within aggressive tumors that exhibit intrinsic resistance to apoptosis. The ROS generated by SDT can initiate a Fenton-like catalytic reaction, accelerating lipid peroxidation and ultimately leading to ferroptotic cell death^[84]. SDT offers the advantage of deeper tissue penetration compared to light-based therapies, making it suitable for larger or deeper-seated tumors. In contrast, chemodynamic therapy (CDT) leverages the intrinsic TME, where transition metal-based nanozymes (e.g., iron, copper, manganese), designed to accumulate selectively in tumor cells, catalyze the conversion of endogenous hydrogen peroxide (H₂O₂) into highly reactive hydroxyl radicals (OH·) via Fenton or Fenton-like reactions. The acidic and H₂O₂-rich conditions within tumors enhance this process, leading to sustained ROS generation and lipid peroxidation, thereby enabling CDT to function as a self-sufficient and effective inducer of ferroptosis, often with strong synergistic potential when combined with other therapies^[85].

Overall, catalytic therapies harness controlled ROS generation to effectively induce ferroptosis through lipid peroxidation. By enabling spatially and temporally targeted tumor cell killing, these approaches offer significant potential to overcome therapeutic resistance. Their integration with existing treatment modalities may represent a promising direction for advancing ferroptosis-based cancer therapies.

3.4 Ferroptosis and its combination with chemotherapeutic and targeted agents

Chemotherapy remains a cornerstone of cancer treatment, yet its efficacy is often limited by drug resistance and systemic toxicity. Emerging research highlights the potential of combining chemotherapy with ferroptosis-inducing agents to overcome these challenges, leveraging the unique mechanisms of ferroptotic cell death to enhance therapeutic outcomes^[86].

3.4.1 Epithelial and organ-based cancers

An innovative antibody-drug conjugate (ADC) coupling RSL3 with trastuzumab has demonstrated selective induction of cell death in human epidermal growth factor receptor 2 positive (HER2+) tumors, preserving the reactive electrophilic chloroacetic group essential for RSL3 function^[87]. Moreover, ADCs offer a strategic advantage by enabling the targeted delivery of cytotoxic payloads, potentially minimizing off-target effects associated with systemic GPX4^[87]. This is particularly important for preserving the function of GPX4-dependent organs such as the brain, kidney, liver, and testis^[88,89]. Combination therapies across cancer types highlight the importance of tumor-specific vulnerabilities. In NSCLC, combining ferroptosis inducers (e.g., erastin, sorafenib) with cisplatin enhances cytotoxicity and overcomes resistance in xenograft models^[90]. Furthermore, in vitro studies show that hydroxychloroquine (HCQ) combined with trametinib disrupts glucose metabolism and mitochondrial function in KRAS- and liver kinase B1 (LKB1)-mutant NSCLC cells^[91]. LSD1, a key regulator of activating transcription factor 4 (ATF4), transferrin receptor 1 (TFRC), and ACSL4, reduces GSH and increases ferroptosis, correlating with tumor burden, making it a promising target both in vitro and in vivo^[92]. In small cell lung cancer (SCLC), SCLC exhibits low antioxidant capacity; suppression of antioxidant-capacity biomarkers (ACBs) sensitizes cells to ROS and ferroptosis in vitro, while thioredoxin reductase 1 (TXNRD1) inhibition exhausts ROS buffering. In treatment-naïve SCLC, non-neuroendocrine cells are ferroptosis-sensitive, and targeting both thioredoxin-dependent neuroendocrine cells and non-neuroendocrine cells improves outcomes in vitro and in vivo^[93-95]. Together, these findings emphasize redox vulnerabilities as key opportunities for ferroptosis-based combination therapies.

In breast cancer, ferroptosis dysregulation is increasingly recognized as important for disease progression and prognosis. In silico analyses by Wu et al. identified 259 ferroptosis-related genes, with fifteen genes such as bromodomain-containing protein 4, arachidonate 15-lipoxygenase (ALOX15), and Solute Carrier Family 1 Member 4 (SLC1A4) serving as independent prognostic markers. Additionally, they reported 1,185 ferroptosis-associated long non-coding RNAs (lncRNAs) and 219 microRNAs (miRNAs), greatly expanding potential biomarkers and therapeutic targets^[96]. Triple-negative breast cancer is an aggressive subtype with limited targeted therapeutic options, in which dysregulation of ferroptosis associated pathways contributes to oxidative stress responses, autophagy-mediated iron and lipid metabolism, immune modulation, and tumor progression. Elevated interferon gamma (IFNγ) levels correlate with improved survival, reflecting its role in both antitumor immunity and ferroptosis sensitization^[97]. In in vitro studies, the combination of JQ1 (a small-molecule bromodomain inhibitor) and bortezomib increases ROS and depletes GSH, while iron chelators inhibit the resulting ferroptosis^[98]. In BRCA1-deficient breast cancer, in vitro findings show that resistance to erastin due to low voltage-dependent anion channel 3 (VDAC3) can be overcome by GPX4 inhibition or by combining poly ADP-ribose polymerase (PARP) and GPX4 inhibitors to induce ferritinophagy^[99,100]. Elevated ferritinophagy flux leads to a greater intracellular labile iron pool, increasing cellular vulnerability to oxidative stress and ferroptosis upon GPX4 blockade.

In gastric cancer, in vitro studies have shown that inhibition of DNA polymerase theta (POLQ), an enzyme involved in error-prone DNA repair, reduces cancer stemness. This effect is potentially mediated through downregulation of dihydroorotate dehydrogenase (DHODH), a mitochondrial enzyme that catalyzes de novo pyrimidine synthesis, thereby supporting nucleotide production and cellular proliferation. Furthermore, the POLQ inhibitor novobiocin exhibits synergistic effects with sulfasalazine against cancer stem cells^[101]. In colorectal cancer (CRC), uridine-cytidine kinase-like 1 (UCKL1) knockdown induces ferroptosis in both in vitro and in vivo models by destabilizing NRF2 and reducing GPX4, FSP1, and SLC7A11 expression, independent of its role in pyrimidine metabolism^[102]. Combining RSL3 with cetuximab re-sensitizes KRAS-mutant CRC in vitro and in vivo via inhibition of the NRF2/HO-1 axis^[103]. In gastrointestinal stromal tumors (GIST), in vitro and in vivo findings demonstrate that imatinib induces ferroptosis through iron accumulation, GSH depletion, and GPX4 degradation, with enhanced efficacy when combined with RSL3^[104]. In hepatocellular carcinoma (HCC), in vitro and in vivo studies have shown that sorafenib promotes ferroptosis in HCC, though resistance arises when GSTZ1 downregulation activates NRF2 and upregulates GPX4; combining sorafenib with RSL3 can overcome this resistance^[105]. Similarly, knocking out CREB-regulated transcription coactivator 3 (CRTC3) sensitizes HCC cells to IFN-γ by increasing PUFA accumulation and lipid peroxidation, thereby enhancing ferroptosis^[106,107]. In pancreatic cancer, Jing et al. together with Li et al. and Grignano et al. showed that dihydroartemisinin (DHA) combined with cisplatin induces ferroptosis through GPX depletion and iron overload in vitro, while inhibiting SLC3A2 N-glycosylation with tunicamycin further amplifies Imidazole ketone erastin (IKE)-induced lipid peroxidation and suppresses tumor growth in orthotopic PANC-1 models in vivo^[108-110]. These studies highlight how targeting ferroptosis pathways, alone or in combination with conventional therapies, offers a promising strategy for liver and pancreatic cancers.

Moreover, it has been shown that ferroptosis is an important vulnerability in reproductive and urinary cancers, including ovarian, cervical, bladder, and prostate cancers, where therapy resistance is common. In ovarian cancer, high FSP1 levels correlate with poor prognosis, and inhibiting FSP1 overcomes PARP inhibitor resistance, even in BRCA-proficient cells. This combination with olaparib showed strong synergy in patient-derived organoids in vitro and was well-tolerated in xenograft models in vivo, though surprisingly, the effect was ferroptosis-independent, arising instead from impaired DNA repair via FSP1-Ku70 interaction^[111]. Conversely, combining Arsenic Trioxide with olaparib in platinum-resistant ovarian cancer induced ferroptosis both in vitro and in vivo, enhancing DNA damage, apoptosis, and lipid peroxidation through AMPKα activation and SCD1 suppression^[112]. These studies underscore the potential of targeting ferroptosis or DNA repair pathways to overcome drug resistance in ovarian cancer. In cervical cancer, targeting the mitochondrial protein, mitochondrial carrier homolog 1 induces ROS-mediated ferroptosis in vitro, which is further enhanced by sorafenib. This synergy is linked to Forkhead Box O1 regulation of GPX4, highlighting a promising therapeutic strategy^[113]. In bladder cancer, Sun et al. showed that the ferroptosis inducer Fin56 triggers GPX4 and ferritin degradation in vitro, a process dependent on autophagy. Combining Fin56 with the mTOR inhibitor Torin 2, which activates autophagy, strongly amplifies cytotoxicity, suggesting a potential combination therapy^[114]. In prostate cancer (PC), RSL3 effectively induces ferroptosis, and its activity is enhanced by iron supplementation both in vitro and in vivo, including in the transgenic adenocarcinoma of the mouse prostate model, a genetically engineered mouse model to study PC development and progression. When combined with the anti-androgen drug Enzalutamide, this three-way regimen significantly inhibits tumor growth and prevents aggressive castration-resistant PCa, demonstrating the potential of ferroptosis-based combination strategies^[115]. Further advances include the discovery of PACMA31, an irreversible inhibitor of protein disulfide isomerase, which can induce ferroptosis. Regorafenib, a multi-kinase inhibitor approved for the treatment of several advanced cancers, has also been identified as a modulator of ferroptosis pathways. Researchers found that regorafenib synergizes with PACMA31, RSL3, and erastin to enhance ferroptosis induction, opening new avenues for combination therapy^[116].

Together, these studies across various tumor models demonstrate that targeting ferroptosis in combination with chemotherapy or targeted therapies exploits tumor-specific vulnerabilities, enhancing oxidative stress and cell death, and holds great promise for improving outcomes across epithelial cancers in both in vitro and in vivo models.

3.4.2 Non-epithelial malignancies

Neuroblastoma, a pediatric tumor of neural crest origin, accounts for around 15% of childhood cancer deaths, with high-risk, MYCN-amplified cases showing poor prognosis^[117,118]. Oncogenic MYCN reshapes metabolism and antioxidant defenses but paradoxically increases ferroptosis susceptibility under cysteine deprivation. Alborzinia et al. showed that limiting cystine and blocking the trans-sulfuration pathway, combined with GPX4 inhibition, induces ferroptosis cell death and drives tumor remission in an orthotopic MYCN-amplified neuroblastoma model^[56,57]. Moreover, genome-wide CRISPR screens further identified LRP8 as essential for ferroptosis resistance by mediating selenocysteine uptake for GPX4 in MYCN-amplified neuroblastoma cells, which rely on LRP8 due to low expression of alternative selenium transporters, highlighting the therapeutic potential of multi-faceted ferroptosis strategies in aggressive neuroblastoma^[57]. Hematological malignancies arise from hematopoietic or immune cells, and somatic or germline mutations in stem or progenitor cells drive clonal expansion and tumor development^[119]. AML, the most common and aggressive form of hematological malignancy, is characterized by uncontrolled proliferation and impaired differentiation, typically treated with chemotherapy (e.g., cytarabine and daunorubicin) or targeted therapy (e.g., venetoclax and azacitidine)^[120]. It has been shown that in vitro inhibition of NRF2 with ML385 enhances venetoclax-induced ferroptosis, suggesting a way to overcome AML drug resistance^[121]. Mitochondrial regulation is critical, as metabolic reprogramming driven by ectonucleotidase CD39 (ENTPD1) enhances mitochondrial biogenesis and oxidative phosphorylation to promote drug resistance^[122], while inhibition of the electron transport chain synergizes with ferroptosis induction, yielding potent antileukemic effects both in vitro and in vivo^[123]. Additionally, DHA induces early ferroptosis by promoting ferritinophagy and increasing intracellular iron, while activating zinc or metallothionein (MT) antioxidant pathways; targeting MT isoforms (e.g., MT2A and MT1M) further boosts efficacy of DHA in AML cells, offering potential combination strategies^[108].

Melanoma cells follow a two-dimensional differentiation trajectory with four subtypes, each of which shows distinct sensitivity to ferroptosis and iron-dependent oxidative stress. It has been shown that cells resistant to MAPK-targeted therapies and immune checkpoint inhibitors are more vulnerable to ferroptosis, making ferroptosis inducers a promising complementary strategy in vitro and in vivo^[55]. Interestingly, invasive MITF^low/AXL^high cells are more ferroptosis-sensitive than proliferative MITF^high/AXL^low cells, though secreted ApoE protects invasive cells by lowering PUFA and increasing GPX4, marking APOE^high tumors as therapy-resistant^[124]. Moreover, lymph-derived melanoma cells experience reduced oxidative stress due to higher glutathione and oleic acid and lower free iron, enhancing metastatic potential^[125]. Sato et al. demonstrated that targeting system Xc^-, strongly suppresses tumor growth and metastasis in mouse models without affecting normal tissue, highlighting its promise as a therapeutic target^[126]. Zhang et al. demonstrated that miR-9 regulates ferroptosis in melanoma by targeting Glutamic-Oxaloacetic Transaminase 1, and its overexpression reduces lipid peroxidation and protects cells, while inhibition increases sensitivity to Erastin and RSL3 in vitro^[127]. Similarly, miR-137 suppresses ferroptosis by targeting the glutamine transporter SLC1A5, and its inhibition enhances responsiveness to ferroptosis inducers in vitro^[128]. 3-hydroxybutyrate dehydrogenase 2 (BDH2), an iron regulator, controls iron transfer at mitochondria lysosome contacts, supporting mitochondrial function and lysosomal pH. Loss of BDH2 leads to lysosomal iron accumulation, sensitizing mesenchymal-like melanoma cells to ferroptosis, whereas restoring BDH2 or adding 2,5-dihydroxybenzoic acid promotes metastasis^[129].

Overall, these observations in neuroblastoma, AML, and melanoma reveal ferroptosis as a key vulnerability across non-epithelial malignancies, with metabolic rewiring, redox regulation, and iron homeostasis influencing sensitivity. Strategic targeting of cystine uptake, GPX4, LRP8, system Xc^-, and regulators like miR-9, miR-137, and BDH2 can effectively tip the balance toward ferroptotic cell death in both in vitro and in vivo models, offering a promising framework for multi-pronged, context-specific therapies against these aggressive cancers. In summary, ferroptosis offers a compelling vulnerability across both epithelial and non-epithelial cancers that can be leveraged to enhance chemotherapy and targeted therapies. By exploiting tumor-specific metabolic and redox weaknesses such as GPX4 dependency, iron handling, system Xc^- activity, and autophagy, ferroptosis inducers synergize with conventional treatments to overcome drug resistance in vitro and in vivo. Overall, integrating ferroptosis-based strategies provides a powerful, adaptable approach to improve therapeutic outcomes across diverse cancer types.

3.5 Ferroptosis and immunotherapy combinations

In recent years, preclinical data, despite some controversial findings, have shown that ferroptosis might represent a promising strategy to complement immunotherapy by reshaping the TME and boosting the anti-tumor immune response. Research indicates that inducing ferroptosis in cancer cells can improve the efficacy of immune checkpoint inhibitors^[130]. However, it is important to note that the relationship between ferroptosis and anti-tumor immunity is complex and highly context-dependent. Demuynck et al. showed that early ferroptotic cells may be immunogenic and could potentially enhance cancer therapy, particularly in tumors resistant to apoptosis or necroptosis. In contrast, Wiernicki et al. demonstrated that as ferroptosis progresses, oxidized lipids and other microenvironmental factors such as lactate, hypoxia, and acidification can impair dendritic cell function, reduce antigen presentation, and promote immune evasion^[131,132]. These findings highlight that while ferroptosis has therapeutic potential, its immunogenicity is not uniform and may vary with timing, tumor context, and microenvironmental conditions, necessitating careful evaluation when designing ferroptosis-based anticancer strategies.

In melanoma, patients with lower SLC3A2 expression showed better clinical outcomes after nivolumab, implying that SLC3A2 might serve as a potential biomarker for melanoma prognosis. Under cystine depletion, checkpoint inhibitors can amplify the anti-tumor effects of T cells as CD8⁺T cells release IFNγ. IFNγ downregulates subunits of the system Xc^-[133,134]. In TNBCs cells, ferroptosis inducers such as erastin, RSL3, and salinomycin upregulate PD-L1 expression, increasing sensitivity to immunotherapy. Patients with lower PD-L1 expression had reduced survival rates, suggesting that PD-L1 and ferroptosis-related genes can be considered prognostic factors^[135]. An intriguing recent study revealed that luminal androgen receptor TNBCs are highly sensitive to ferroptosis. Combining GPX4 inhibitors such as RSL3 and ML162 with anti-PD-1 therapy was significantly more effective than either treatment alone, suggesting that this combination could represent a novel treatment strategy for this aggressive breast cancer subtype^[136].

Metabolic reprogramming plays a critical role in tumorigenesis and cancer immunotherapy. Lipid, fatty acid, and cholesterol metabolism influence CD8⁺T cell activity and overall immune response. For instance, Liao P et al. showed that arachidonic acid supplementation has been shown to stimulate tumor ferroptosis and synergize with checkpoint therapy. Low-dose arachidonic acid administration inhibited tumor growth in various mouse models, including those resistant to immune checkpoint blockade, and improved the efficacy of PD-L1 blockade by enhancing the anti-tumor T cell response via the IFNγ signaling pathway. Future research is needed to explore the roles and mechanisms of various fatty acids and their combinations in promoting tumor cell ferroptosis^[137]. The integration of immunotherapy and ferroptosis induction represents a groundbreaking approach to cancer treatment, offering a dual mechanism to overcome resistance and improve therapeutic outcomes. This synergy is increasingly being evaluated in clinical settings. For instance, the multi-kinase inhibitor sorafenib, which also functions as system Xc^- inhibitor^[138], is being investigated and is in a phase Ib/II trial in combination with pembrolizumab (anti-PD-1) for advanced hepatocellular carcinoma (NCT03211416)^[22,139], leveraging the ability of ferroptotic cells to enhance the immunogenicity of the TME. Similarly, sulfasalazine, another repurposed SLC7A11 inhibitor, is under clinical evaluation in metastatic colorectal cancer (NCT06134388)^[140] and has shown promise in enhancing anti-tumor immunity when combined with other modulators.

Collectively, these findings in immunotherapy suggest that ferroptosis can potentiate immune checkpoint blockade and reshape the TME. However, its immunological effects are highly context-dependent, as early ferroptotic cells may enhance antigen presentation and T cell activation, whereas late ferroptotic cells can impair immune function through the accumulation of oxidized lipids and immunosuppressive metabolites. Mechanistically, ferroptosis induction can synergize with immunotherapy by modulating pathways such as IFNγ signaling and system Xc^- inhibition, thereby increasing tumor cell susceptibility to CD8⁺ T cell-mediated killing^[141]. In addition, ferroptosis-associated regulators such as SLC3A2, together with immune checkpoint proteins such as PD-L1 (CD274), may serve as complementary biomarkers reflecting tumor metabolic state and immune evasion, respectively, and may help predict responses to immune checkpoint inhibitors. Overall, combining ferroptosis induction with immunotherapy holds significant promise for overcoming resistance and improving clinical outcomes, particularly in difficult-to-treat cancers (Figure 4).

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Figure 4. Molecular mechanisms of ferroptosis and combination therapies: This figure outlines the molecular mechanisms underlying ferroptosis and highlights various drug combinations that enhance cytotoxicity in cancer cells through concurrent targeting of distinct cellular pathways. The key combination includes JQ1 with bortezomib, Erastin/PACMA31 with Methotrexate, and multiple pairings involving RSL3 such as with Regorafenib, Erastin, Fulvestrant, Trastuzumab, and others. Additionally, combinations like neratinib with trastuzumab, Digoxin with sulfasalazine, and cisplatin with dihydroartemisinin, demonstrate the potential in increasing therapeutic efficacy. These strategies underscore the promise of leveraging ferroptosis in combination therapies to improve treatment outcomes in cancer. Created in BioRender. Trumpp, A. (2026) https://BioRender.com/eup5h9n. RSL3: RAS synthetic lethal compound 3; ROS: reactive oxygen species.

3.6 Ferroptosis and radiotherapy combinations

Ferroptosis has also been identified as a potent mechanism to enhance the efficacy of RT by sensitizing cancer cells to oxidative stress and overcoming resistance. RT primarily exerts its cytotoxic effects through the generation of ROS and other free radicals^[142]. Specifically, ionizing radiation (IR) induces radiolysis of water, forming highly reactive species like hydroxyl radicals, superoxide radicals (O₂·^–), and hydrogen peroxide (H₂O₂)^[143,144]. Depending on the specific species generated and their intracellular location, these free radicals damage cellular macromolecules, leading particularly to the lipid peroxidation of PUFAs within cell membranes, which is a hallmark of oxidative stress and a key mechanism of ferroptosis. This process generates lipid hydroperoxides and reactive aldehydes, which are key drivers of ferroptosis^[143,145]. At physiological concentrations, however, certain ROS, such as hydrogen peroxide and superoxide, also serve as signaling molecules in redox regulation, whereas excessive ROS generation leads to oxidative stress and promotes lipid peroxidation and ferroptotic cell death[^146]. In line with this, Ye et al. showed that ferroptosis inducers act as radiosensitizers across multiple cancer types, amplifying the effects of radiation on cytoplasmic lipid peroxidation and cell death in vitro, which also enhanced the antitumor effect of radiation in murine xenograft models and human patient-derived models of lung adenocarcinoma and glioma^[145]. This approach could pave the way for the first clinical trial focusing on ferroptosis^[145].

In KEAP1 mutant lung cancers, FSP1 suppresses ferroptosis and reduces the anti-tumor effects of radiation. Blocking FSP1 with iFSP treatment sensitized KEAP1-deficient and mutant lung cancer cells to RT, while inhibiting ferroptosis with ferrostatin-1 diminished the radio-sensitizing effect of iFSP. These findings suggest that combining ferroptosis induction with RT could be a potent therapeutic strategy for various cancers^[147]. IR triggers ferroptosis in cancer cells by elevating ROS and upregulating ACSL4 expression, which drives the production of PUFA-containting phospholipids that are highly susceptible to lipid peroxidation. Although the mechanism of ACSL4 induction remains unclear, it may involve radiation-responsive factors such as p53 or BRCA1-Associated Protein 1. Inhibition of ACSL4 blocks IR-induced lipid peroxidation and ferroptosis, leading to radio resistance. IR also upregulates ferroptosis inhibitors such as SLC7A11 and GPX4. These findings, demonstrated in multiple cancer cell lines and xenografts/PDX models, show that enhanced ferroptosis correlates with improved radiotherapy response and patient survival^[148].

Sulfasalazine, a system Xc^- inhibitor, has radiosensitizing effects in Colorectal cancers. Under hypoxic conditions, system Xc^- is upregulated, making cancer cells more dependent on its function to protect against ROS and ferroptosis. Inhibiting system Xc^- with sulfasalazine in these conditions increases sensitivity to ROS and RT. In colorectal adenocarcinoma, combining sulfasalazine with RT delayed tumor growth more effectively than either treatment alone, suggesting sulfasalazine could serve as a neoadjuvant chemoradiation agent^[149]. The tumor suppressor TP53 plays a critical role in mediating radiosensitivity by increasing vulnerability to ferroptosis. Xu and colleagues showed that p53 suppresses SLC7A11 expression and enhances sensitivity to ferroptosis^[150]. Nutlin and RG7112, both MDM2 inhibitors, promote p53 expression, increasing cancer cell sensitivity to RT and lipid peroxidation in lung cancer cells. In p53-deficient cancer cells, sulfasalazine, erastin, or RSL3 can synergize with RT-mediated lipid peroxidation, suggesting that combining ferroptosis induction with RT may amplify cytotoxicity in p53-mutant cancers. Current research primarily focuses on X-rays (low-linear energy transfer (LET) radiation), which remains the global standard. However, proton therapy and other particle-based treatments have demonstrated superior therapeutic efficacy in specific cases due to their precision dose deposition, which minimizes collateral damage to normal tissues, rather than a superior biological effect (high LET) alone. Recent studies have demonstrated that X-ray induced in-situ ferroptosis, catalyzed by iron-based nanomaterials, provides a safer and more localized method for inducing ferroptosis, minimizing systemic toxicity while maximizing the anti-tumor effect of radiotherapy^[151,152]. Given the distinct biological effects of different radiation types, the regulation of ferroptosis requires further investigation to elucidate its role across these various particles^[153]. In summary, ferroptosis enhances treatment efficacy by amplifying radiation-induced oxidative stress and lipid peroxidation in cancer cells. IR generates ROS that initiate ferroptotic cell death, while ferroptosis inducers further sensitize tumors and improve responses in preclinical models. Key regulators such as SLC7A11, GPX4, ACSL4, FSP1, and TP53 critically influence this process, with their modulation helping to overcome radioresistance. Overall, integrating ferroptosis with radiotherapy offers a promising strategy to enhance therapeutic outcomes, although further clinical validation is required.

3.7 Nutritional interventions and ferroptosis

Dietary strategies in cancer therapy are increasingly being explored, though their effects remain debated. This is due to complex interactions between tumor biology, including genomic instability, metabolic plasticity, and host factors, such as immunity, and the gut microbiome, and treatment tolerance^[154]. This challenge calls for precision nutrition strategies that integrate molecular profiling, therapy type, and individual metabolic phenotypes. Evidence suggests that periodic fasting and fasting-mimicking diets (FMDs) can protect healthy cells while sensitizing cancer cells, improving therapy outcomes^[155]. For example, a randomized trial of HER2-negative breast cancer patients found that FMDs reduced grade III vomiting and neutropenia, improved erythrocyte and neutrophil counts, lowered IGF-1 and hs-CRP, and enhanced pathological and radiological responses compared to controls^[156]. Similarly, the ketogenic diet (KD), which is high in fat and low in carbohydrates, mimics fasting, deprives cancer cells of glucose, and enhances chemotherapy effectiveness^[157].

Targeted nutrient-specific restrictions, particularly amino acid restriction, can inhibit cancer cell proliferation^[158], while immunomodulating enteral nutrition (arginine, omega-3, nucleotides) improved body weight, albumin, nutritional risk index, and plasma antioxidant capacity in a double-blind trial of 37 head/neck and esophageal cancer patients^[159]. Micronutrients such as selenium and vitamin E also modulate oxidative stress and ferroptosis, suggesting that personalized nutritional strategies could complement conventional and ferroptosis-based therapies (Figure 5).

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Figure 5. The role of bioactive compounds and nutrients in iron homeostasis and ferroptosis regulation. This figure illustrates how various bioactive compounds and nutrients influence intracellular iron homeostasis, redox balance, and ferroptosis. Notably, Vitamin C facilitates iron accumulation while depleting GSH, and vitamin D similarly promotes iron overload and suppresses the expression of SLC7A11. The metabolism of polyunsaturated fatty acids can lead to increased lipid substrates prone to pro-oxidative damage. In contrast, selenium, vitamin K, and vitamin E are depicted as key antioxidants, offering protective effects against oxidative stress. Together, these compounds and nutrients demonstrate a complex interplay in regulating cellular responses associated with ferroptosis and oxidative stress. Created in BioRender. Trumpp, A. (2026) https://BioRender.com/eup5h9n. GSH: glutathione; ROS: reactive oxygen species; DHA: dihydroartemisinin.

3.7.1 Selenium

Selenium is an essential micronutrient crucial for redox regulation, primarily through its incorporation into selenoproteins, a family of 25 human proteins that contain the amino acid selenocysteine^[12]. Selenocysteine is essential for antioxidant enzymes like GPX4, and selenium depletion increases cellular sensitivity to ferroptosis by reducing GPX4 activity^[160]. Conversely, selenium supplementation can protect cells from ferroptotic damage^[161]. Ingold et al. showed in vivo that replacing GPX4 selenocysteine with cysteine causes fatal neurodegeneration, confirming the vital role of selenium in cellular and neuronal survival^[160]. However, multiple preclinical studies show that selenium-restricted diets are well-tolerated in mice^[162]. In an earlier study by Klaus and colleagues, selenium-depleted mice were completely resistant to pristane-induced plasmacytoma development, primarily due to the inhibition of inflammatory granuloma formation and reduced responsiveness of immune cells to chemoattractants, suggesting that selenoproteins may play a critical role in promoting inflammation-driven tumorigenesis^[162]. Recently, Freitas and colleagues showed that depriving NSG mice of selenium for several weeks had no major impact on their overall health. Notably, however, in this xenograft model, lymphoma tumor growth was significantly reduced in the selenium-restricted group^[4]. Clinical studies show that selenium supplementation can mitigate RT-induced toxicities in cancer patients. In a randomized controlled trial of 81 cervical and uterine cancer patients, selenium-deficient individuals receiving sodium selenite had higher serum selenium levels and experienced less severity of RT-induced diarrhea^[163]. Another study in cervical cancer reported reduced Grade ≥ 2 diarrhea and Grade 3 myelosuppression with supplementation, especially in selenium-deficient or moderately differentiated tumors^[164]. Beyond toxicity mitigation, selenium influences cancer progression. Mouse studies indicate that selenium deprivation can prevent inflammation-driven plasma cell tumors by impairing inflammatory tissue formation, suggesting that selenoproteins may promote inflammation-associated cancers^[162].

In AML, oncogenic enhancers upregulate SEPHS2 to drive selenoprotein production, creating a therapeutic vulnerability. Both genetic SEPHS2 knockout or dietary selenium restriction delayed leukemogenesis in mice and enhanced chemotherapy efficacy without affecting normal hematopoiesis^[165]. Recent studies identified two key regulators of selenium uptake and metabolism, PRDX6 and LRP8, which also influence ferroptosis. In vivo, knockout of PRDX6 and SCLY in neuroblastoma xenografts impaired tumor growth and reduced GPX4 levels. Importantly, high PRDX6 expression in PDX models correlated with tumor progression, treatment resistance, and poorer survival outcomes, highlighting the therapeutic value of these pathways^[166-168]. In an orthotopic neuroblastoma mouse model, genetic deletion of the selenocysteine receptor LRP8 severely impaired tumor initiation and growth^[57]. Modulating selenium metabolism through these pathways may open new avenues for selectively inducing ferroptosis in tumor cells while sparing normal tissues.

3.7.2 Vitamins

Vitamin E is a potent antioxidant that inhibits ferroptosis by scavenging lipid peroxyl radicals and preventing the spread of lipid peroxidation, thus protecting cells from oxidative damage^[169]. However, this protective effect might interfere with cancer treatments that aim to induce ferroptosis in tumor cells^[170]. Studies have shown that vitamin E can suppress ferroptosis both in vivo and in vitro^[58,171]. In vivo, hematopoietic GPX4 deletion in mice impairs reticulocyte maturation, causes anemia, and leads to iron dysregulation; this effect is worsened by vitamin E deficiency but partially rescued by supplementation, highlighting its protective role^[172]. Overall, these findings emphasize that although vitamin E supports normal cell survival, its use during cancer therapy may need to be carefully considered, as it could unintentionally protect tumor cells. Recent discoveries show that reduced forms of vitamin K, including menaquinone and phylloquinone, exhibit potent anti-ferroptotic activity beyond their well-characterized role in coagulation. These compounds function as effective radical-trapping antioxidants, directly inhibiting phospholipid peroxidation through redox cycling of their hydroquinone forms. FSP1 plays a key role by reducing vitamin K to its hydroquinone form, which inhibits ferroptosis. In vivo, combining vitamin K derivatives with α-tocopherol (vitamin E) in GPX4-deficient mouse models suggests synergistic antioxidant effects^[173]. Mechanistically, vitamin K hydroquinone regenerates α-tocopherol from its radical form, sustaining antioxidant activity, as confirmed using the LipiRADICALGreen assays. Importantly, in vivo studies using pharmacological doses of vitamin K, specifically MK4, demonstrated strong protection against ferroptosis in liver and kidney injury models, reducing tissue damage and improving organ function^[173].

Unlike vitamin E, which plays a protective role against oxidative damage and ferroptosis, the role of vitamin C (ascorbate) remains controversial; however, it has gained renewed interest as a potential cytotoxic agent due to its unique redox properties and selective effects in tumors harboring specific genetic mutations^[174,175]. It has been shown that at high doses, vitamin C generates hydrogen peroxide, and its efficacy appears enhanced under selenium-deficiency, suggesting dietary modulation could improve therapeutic outcomes^[176]. Clinical and epidemiological data support this, as higher vitamin C intake is associated with improved survival in colorectal cancer patients with KRAS or BRAF mutations^[177]. A phase II trial in metastatic pancreatic cancer indicates that high-dose vitamin C may induce synthetic lethality in RAS-mutant tumors when combined with chemotherapy^[178]. Mechanistically, vitamin C also influences ferroptosis by enhancing iron uptake and disrupting redox balance^[179,180]. In vitro, high-dose vitamin C combined with erastin enhances ferroptosis in pancreatic cancer cells by increasing ROS, depleting GSH, and elevating iron levels. In vivo, this combination significantly suppressed tumor growth in mouse models without harming major organs, highlighting its therapeutic potential^[181]. Overall, vitamin C shows promise as a widely accessible anticancer strategy, although further work is needed to define predictive biomarkers and optimize patient selection^[182].

Recent studies indicate that vitamin D might promote ferroptosis, especially in colorectal cancer stem cells. Guo and colleagues showed that vitamin D downregulates SLC7A11, reducing cystine uptake and glutathione levels, which increases ROS and triggers ferroptotic cell death both in vitro and in nude mouse models^[183]. In addition, vitamin D also disrupts iron homeostasis by suppressing hepcidin expression, contributing to oxidative stress and cell death^[184]. Together, these findings suggest that vitamin D enhances ferroptosis sensitivity by targeting both antioxidant defenses and iron metabolism ; further studies are needed to fully explore its therapeutic potential.

In addition to selenium and vitamins, other dietary components such as polyphenols, fatty acids, and amino acids participate in regulating ferroptosis through their effects on oxidative stress, lipid metabolism, and iron homeostasis. Polyphenols like Resveratrol and epigallocatechin gallate promote ferroptosis in colorectal and NSCLC cells by increasing ROS and lipid peroxidation through downregulation of key regulators such as SLC7A11 and GPX4^[185,186]. These effects suggest their potential use alongside ferroptosis inducers to enhance cancer therapy. PUFAs, specifically omega-3 and omega-6, also influence ferroptosis, particularly in acidic tumor environments. Dierge et al. demonstrated that these fatty acids can selectively induce ferroptosis in human colorectal carcinoma (HCT-116) cells via TGFβ2 signaling and CD36-mediated fatty acid uptake^[187], leading to lipid droplet accumulation and subsequent lipid peroxidation. In vivo, omega-3 PUFA-rich diets slowed tumor growth in HCT-116 models, particularly when combined with lipid droplet inhibitors or ferroptosis inducers^[187,188]. Overall, these findings highlight the potential of dietary components to sensitize cancer cells to ferroptosis, although clinical studies are needed to validate their therapeutic application.

In mouse models of pancreatic ductal adenocarcinoma (PDAC), deletion of the cystine transporter subunit Slc7a11 or treatment with cyst(e)inase induced tumor-selective ferroptosis and suppressed PDAC growth^[54]. This vulnerability arises from the strong dependence of PDAC cells on cysteine for glutathione and coenzyme A synthesis, both essential for maintaining redox homeostasis and preventing lipid peroxidation^[54]. Engineered cyst(e)inase effectively depletes extracellular cysteine and cystine, selectively impairing cancer cell survival, and has broad anti-tumor activity in preclinical models of multiple cancer types, including prostate, breast, and leukemia^[189]. Additionally, combined cysteine and methionine deprivation (CMD) synergizes with GPX4 inhibition (via RSL3) to potentiate ferroptotic cell death and lipid peroxidation in both murine and human glioma models. In vivo, a CMD diet significantly enhanced the therapeutic efficacy of RSL3 and extended survival in the glioma mouse model^[190].

Overall, nutritional interventions play a complex but powerful role in regulating ferroptosis in cancer therapy, as shown in various preclinical models with effects that depend on both tumor biology and host metabolism. Dietary strategies such as fasting, KDs, and amino acid restriction can sensitize cancer cells to ferroptosis and improve treatment responses. Micronutrients show dual roles, where selenium and vitamins E or K generally inhibit ferroptosis, while vitamins C and D can promote it by increasing oxidative stress and altering iron metabolism. Other dietary components, including polyphenols, PUFAs, and cysteine-targeting approaches, further enhance ferroptosis in vitro and in vivo across multiple cancer models. Importantly, these effects are highly context-dependent, requiring careful integration with existing therapies.

4. Challenges

4.1 Tumor specificity

Preclinical studies demonstrate ferroptosis as a promising anticancer strategy; however, clinical translation faces significant challenges. Although the search for more specific and effective compounds for preclinical studies is ongoing in the field of ferroptosis, key obstacles include achieving tumor-specific induction, identifying predictive biomarkers, and understanding resistance mechanisms. A fundamental challenge, as with any novel targeted therapy or cell death mechanism, lies in achieving selective effects against malignant cells while preserving healthy tissues. This selectivity is crucial to minimize potential side effects.

4.2 Biomarkers and patient stratification

Ferroptosis sensitivity is not uniform across all cell types or conditions; rather, it is subject to intricate context-dependent regulation. Factors such as the specific cancer cell type, the metabolic state of the cell, and the surrounding TME can significantly influence the susceptibility to ferroptotic cell death^[191]. For example, the tumor suppressor p53 is a central regulator of cell fate, governing processes such as cell cycle arrest, senescence, DNA repair, and multiple forms of cell death. p53 acts as a bidirectional regulator of ferroptosis through canonical and noncanonical pathways by modulating iron metabolism, lipid peroxidation, glutathione homeostasis, and ROS levels. These insights highlight the importance of ferroptosis in p53-driven tumor suppression, and consistent with this regulatory role, p53-mediated ferroptosis also contributes to enhanced radiosensitivity in cancer cells^[150]. These context-dependent regulatory features underscore the need for robust biomarkers to predict ferroptosis sensitivity across different tumor settings. The discovery of reliable biomarkers to predict and monitor ferroptosis in patients could greatly improve the clinical use of therapies aimed at inducing this form of cell death, facilitating personalized treatment plans tailored to individual patient profiles. Further investigation into the specific molecular processes of ferroptosis across various disease contexts is necessary. This includes conducting clinical trials to assess the safety and effectiveness of ferroptosis-inducing combination therapies, which is also essential. Importantly, key regulators such as MYC, p53, and KRAS add an additional layer of complexity, as they can exert bidirectional control over ferroptosis through modulation of glutathione metabolism, lipid peroxidation, iron, and ROS levels. This suggests that single-parameter biomarkers may be insufficient, and that integrated approaches combining genetic, metabolic, and redox features will be required. In line with the importance of redox and metabolic context, Samarin and colleagues identified ACBs. Identifying cancers with lower ACB expression might improve the success rate of clinical trials for redox-targeting drugs. This biomarker-driven approach will be key to selecting patients most likely to respond to ferroptosis-based therapies, ultimately enhancing therapeutic efficacy^[94]. Recent work in neuroblastoma highlights ferroptosis as a therapeutic avenue, particularly in MYCN-amplified cases. A four-gene signature (LIFR, TP53, NRAS, OSBPL9) was identified, predicting poor survival and validated experimentally. This model offers both prognostic value and potential therapeutic targets^[192].

4.3 Resistance mechanisms and delivery strategies

Understanding and addressing the mechanisms of resistance to ferroptosis is crucial for creating effective combination treatments. Resistance to ferroptosis may arise from multiple mechanisms, including dysregulation of iron metabolism and redox homeostasis, as well as upregulation of protective pathways in cancer cells. For example, as discussed earlier in this review, EMT-mediated changes in lipid metabolism have been linked to greater susceptibility to ferroptosis in cancer cells^[62]. Moreover, there is a need to determine which cancer subtypes harboring a particular genetic background exhibit greater sensitivity to ferroptosis, given that biomarkers remain limited, and to identify potential synergies with existing treatments. In this context, studying the intricate interplay of iron metabolism and associated molecular regulators, such as hepcidin, TFR2, and ferritin, will be invaluable^[193]. These factors not only regulate iron homeostasis but also influence ferroptosis susceptibility in various cancer types. By further understanding these relationships, we can better refine strategies to exploit ferroptosis as a therapeutic strategy.

In addition, current research shows great potential for treating cancers more effectively by providing more targeted combinations of ferroptosis-inducing therapies, other targeted therapies, and newer delivery strategies such as antibody-drug conjugates and nanoparticles. These platforms enhance tumor specificity by enabling more selective delivery of therapeutics to cancer cells, thereby improving efficacy while reducing off-target toxicity. For example, combining the GPX4 inhibitor with trastuzumab in HER2-positive breast cancer cells selectively eliminated tumor cells, demonstrating improved therapeutic efficacy with reduced non-specific effects^[87,194,195]. Beyond GPX4 inhibition, upstream regulation of ferroptosis through glutathione biosynthesis has recently emerged as an underexplored but promising target for ferroptosis induction. Inhibition of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis, has been shown to trigger potent and selective ferroptotic cancer cell death. Novel GCL inhibitors such as KOJ-1 and KOJ-2 exhibit strong cellular activity and favorable pharmacological properties, providing both useful research tools and potential therapeutic candidates for glutathione-targeted ferroptosis strategies^[196]. Further research into agents with increased selectivity for cancer cells, and further differentiation between normal cells and malignant cells at the molecular levels is necessary. An overview of ferroptosis-based treatment strategies, including the compounds used, underlying mechanisms, and cancer types evaluated across in vitro, in vivo, and early clinical studies is summarised in Table 1.

5. Future Perspectives and Conclusion

Given the diverse molecules and pathways that can independently initiate and promote ferroptosis, this cell death modality represents a novel therapeutic target with significant potential for combination cancer therapies^[197]. One of the major challenges in translating these findings into preclinical and clinical practice is the limited number of pharmacologically viable ferroptosis inducers suitable for preclinical use. Moreover, many preclinical studies are still performed using immunocompromised mouse models, which do not adequately capture the complex interactions between ferroptosis and the immune system. The use of animal models where the immune system is intact is important to understand how the TME and immune response can modulate ferroptosis sensitivity and resistance. Elucidating the role of nutritional molecules, including selenium, polyunsaturated fatty acids, iron, and vitamins in modulating ferroptosis represents a pivotal area of future research. However, the clinical translation of these combinatorial approaches faces considerable challenges. Key hurdles include establishing standardized, safe, and effective nutritional protocols and identifying robust predictive biomarkers for accurate patient stratification in clinical trials.

In conclusion, this review has elucidated the intricate mechanisms governing ferroptosis, including the core GPX4-System Xc^-, and FSP1 axes, alongside the critical role of iron metabolism. We have highlighted how cancer cells exhibit specific vulnerabilities to ferroptosis induction and discussed the importance and exciting potential of predictive biomarkers for ferroptosis sensitivity. Emerging catalytic therapies (PDT, SDT, CDT) offer innovative approaches to induce ferroptosis with spatial and temporal precision. Furthermore, ferroptosis-based combination therapies with chemotherapy, immunotherapy, radiotherapy, and targeted therapy show immense potential to overcome drug resistance and enhance therapeutic efficacy (Figure 6). While challenges remain in clinical translation, particularly regarding systemic toxicity and robust biomarker development, ongoing research into novel targets, advanced delivery systems, and personalized medicine approaches promises to unlock the full therapeutic potential of ferroptosis in cancer treatment. Future research should prioritize the development of novel, clinically viable ferroptosis inducers, validated in advanced animal models that faithfully recapitulate human tumor biology. Progress in this field will further depend on optimizing combination regimens, including the careful management of toxicity, pharmacokinetics, and pharmacodynamics and the discovery of robust predictive biomarkers. Addressing these specific challenges is imperative for successfully leveraging ferroptosis as a viable therapeutic strategy in clinical oncology.

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Figure 6. Ferroptosis in combination cancer therapies: This figure shows how ferroptosis interacts with different cancer treatments. The central circle represents ferroptosis mechanisms, while the four surrounding circles show major therapy types: chemotherapy (pink), immunotherapy (green), radiotherapy (light purple), and targeted therapy (dark purple). The overlapping areas highlight key synergistic effects: drug synergy with chemotherapy, enhanced immune recognition with immunotherapy, oxidative stress amplification with radiotherapy, and pathway-specific vulnerability with targeted therapy. Dietry intervention (selenium, vitamins) and clinical translation pathways are shown at the bottom (blue). Created in BioRender. Trumpp, A. (2026) https://BioRender.com/eup5h9n.

Authors contribution

Kaushal K, Sadeghipour S: Investigation, visualization, writing-original draft, writing-review & editing.

Rafiei F: Conceptualization, investigation, visualization, writing-original draft, writing-review & editing.

Marvast SMH, Kumar DR, Gross LZF, Wachter WJ III, Ghosh B, Trumpp A, Mandegary A: Writing-review & editing.

Alborzinia H: Supervision, writing-review & editing.

Conflicts of interest

The authors declare no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by the Deutsche Forschungsgemeinschaft (DFG) SPP2306 (Grant No. AL 1533/5-1 to Hamed Alborzinia), and the Jose Carreras Leukämie Stiftung (Grant No. DJCLS 04 R 2024 to Hamed Alborzinia).

Copyright

© The Author(s) 2026.