Ferroptosis in gastrointestinal stromal tumors

Gastrointestinal stromal tumors (GIST) are the most common malignancies of mesenchymal origin in the gastrointestinal (GI) tract. They are molecularly defined by activating mutations in KIT (~85%) or PDGFRA (5–10%), which directly inform therapeutic strategies. The risk of recurrence can be estimated via tumor size, site of origin, tumor rupture and mitotic index (1). Beyond initial surgical resection, receptor tyrosine kinase (RTK) inhibitors play a major role in the adjuvant as well as in the metastatic setting. Adjuvant Imatinib is the standard for high-risk patients defined by tumor size, mitotic count and tumor site according to the National Institute of Health criteria (2), while not being indicated as standard for all patients. In patients with PDGFRA D842-mutant tumors, avapritinib is effective in the metastatic situation (3). Furthermore, in case of Imatinib intolerance or non-sensitive mutation, Sunitinib (4), Regorafenib (5) or Ripretinib (6) provide subsequent-lines options. However, secondary resistance to RTK inhibition poses a major problem, highlighting the need for developing novel strategies for therapeutic intervention (7). This is particularly true for metastatic GIST.

Pharmacological cancer treatment aims at the induction of tumor cell death. Several mechanisms of cell death have been identified, including apoptosis, necrosis and autophagy, with the underlying biochemical and molecular pathways being known in great detail. More recently, non-apoptotic regulated cell death (RCD) modalities such as ferroptosis and cuproptosis have gained attention, reflecting expanding therapeutic interest in redox-driven vulnerabilities.

The paper Feng et al. (8) particularly focuses on ferroptosis in GIST, induced through the natural compound toosendanin (TSN). TSN, an alkaloid derived from traditional Chinese medicine, has previously demonstrated anti-proliferative and pro-apoptotic effects across multiple tumor entities (9).

Ferroptosis is an iron-dependent form of cell death that is driven by lipid peroxidation. First described in 2012 (10), ferroptosis is now defined by three interconnected axes: (I) the availability and remodeling of polyunsaturated fatty acid-containing phospholipids, which provide the substrates for lethal lipid peroxidation; (II) intracellular iron handling and redox cycling, which fuel the generation of reactive oxygen species (ROS); and (III) antioxidant defence systems, prominently including the system Xc-glutathione-GPX4 axis as well as parallel protective modules such as FSP1-CoQ10 and GCH1-BH4 pathways (11-13). The intricate intracellular balance between these pro-oxidant and protective anti-oxidant mechanisms determines cellular susceptibility to ferroptosis. Importantly, ferroptosis has been shown to play functional roles in tumorigenesis and tumor progression (14), including gastrointestinal cancers (15). Several key players in the context of ferroptosis-induced lipid peroxidation have been identified (16). These include PUFAs, i.e., polyunsaturated fatty acids embedded in the lipid membrane and acting as substrates for lipid peroxidation, GSH (glutathione), GPX4 (glutathione peroxidase 4), ACSL4 (acyl-CoA synthetase long-chain family member 4), SLC7A11 (solute carrier family 7 member 11) and NRF2 (nuclear factor erythroid-2-related factor 2) directly regulating the expression of SLC7A11, ferritin and GPX4. Lipid peroxidation can be mediated enzymatically by iron-dependent lipoxygenases (LOXs) or non-enzymatically through the Fenton reaction, generating highly reactive hydroxyl radicals (17). Their presence can lead to a chain reaction, eventually resulting in lipid peroxidation and subsequent membrane degradation and cell death.

Other studies have also shown the pivotal role of mitochondria in ferroptosis. On the one hand, they act as an important site for iron metabolism, ROS production, and lipid peroxidation, and may play a central role in ferroptosis induction by cysteine deprivation (18). On the other hand, they also harbor ferroptosis defense mechanisms. Erastin—the first described ferroptosis inducer—does not only block SLC7A11 (the major subunit of system Xc−) at the cell membrane, but also targets voltage-dependent anion channels 2 and 3 (VDAC2 and 3) at the outer mitochondrial membrane, leading to aberrant ROS production by the electron transport chain—an effect that can be abrogated by mitochondrial ROS scavengers like MitoTEMPO (19). On the contrary, coenzyme Q10—an important ferroptosis defence molecule used by FSP1—is generated via dihydroorotate dehydrogenase (DHODH) at the inner mitochondrial membrane (20).

The complexity and interplay between these processes thus highlight the relevance of the balance between the cell death-inducing and pro-survival arms. But why would tumor cells be particularly prone to ferroptosis-inducing agents? It is well known that tumor cells systematically remodel their metabolic networks (21). This includes lipid composition of the cell membrane, in particular the content of MUFAs (monounsaturated fatty acids) versus PUFAs, as well as amino acid addiction and redox defense, mitochondrial integrity and quality control, increased iron uptake and storage, and the dependence on antioxidant systems due to high ROS levels, among others. The disruption of these pathways compromises cellular homeostasis and sensitizes tumor cells to cell death including ferroptosis. On the other hand, multiple oncogenic transcription factors or other oncogenes like the RTK HER3 (22) act on ferroptosis inhibition. This indicates that evading these pathways is a critical hurdle for tumor progression.

Nuclear receptor coactivator 4 (NCOA4) is a central regulator of iron metabolism. It is able to recognize and bind to ferritin—an intracellular iron storage protein—and thereby targets it for degradation in the lysosome. The concomitant massive release of iron ions functions as catalyst for the above-mentioned Fenton reaction (23) and eventually the induction of ferroptosis by creating free radicals. In this context, the paper Feng et al. (8) analyzed the role of TSN on the regulation of the NCOA4 ferritinophagy pathway. More specifically, they found that TSN leads to the upregulation of NCOA4 (and LC3 II/I) and in parallel downregulates the ferroptosis key defence enzymes GPX4 and SLC7A11. This induced ferroptosis in the cell line GIST-T1, as shown by increased ROS and iron content. On the cellular level, decreased cell viability, colony formation, migration and invasion were observed. Notably, the siRNA-mediated knockdown of NCOA4 led to an—at least partial—rescue, indicating the direct dependence on NCOA4 for ferroptosis induction. TSN exerted multiple cellular and molecular effects in parallel. While reduced cell viability were probably to be expected, other effects may not be so straightforward, e.g., inhibition of migration. Considering the clinical importance of (inhibiting) GIST cell migration and metastasis, typically within the abdomen, this may be equally relevant.

Some limitations, however, should be noted as well. The experiments in this paper (8) were only done in one cell line. Thus, it remains to be seen to what extent the TSN findings will apply for GIST more generally, since the observed effects may well depend on expression levels of key players in ferroptosis induction, ferroptosis prevention and lipid peroxidation, and therefore might be context dependent. One cell line may probably not sufficiently reflect the inter- and intra-tumor heterogeneity that is frequently seen in GI tumors including GIST (24). In fact, albeit most GIST show mutations in one defined gene (KIT), tumor heterogeneity has been recognized as major issue in GIST therapy, highlighting therapeutic implications based on distinct GIST molecular subtypes (24).

Furthermore, the study relies primarily on increased ROS levels, iron accumulation and changes in GPX4 and SLC7A11 expression. These are suggestive, but not specific indicators of ferroptosis. While the validation of ferroptosis mainly relied on ferrostatin-1 rescue experiments, this could be extended towards other ferroptosis inhibitors or iron chelators. This may be particularly informative since the employed apoptosis assays (Annexin V/7-AAD) do not distinguish between different forms of cell death including apoptosis.

Also, experiments in classical two-dimensional (2D) cell culture do not monitor effects of the tumor microenvironment (TME). The TME, however, has been shown to be of major relevance in tumor growth as well (25). As in other tumors, the GIST TME is a complex mix of immune cells including tumor-infiltrating lymphocytes (TILs), primarily T cells, and tumor-associated macrophages, as well as stromal components and various ligands acting as signaling molecules. The TME affects tumor growth and treatment response to a significant extent, and may for example exert ferroptosis inhibition based on altered GSH levels (see below). A dense ECM may thus not just limit drug penetration, but also counteract the induction of ferroptosis by providing high GSH levels and direct chelators of metal ions, thus acting as key defense line for tumor cells against oxidative stress and ferroptosis.

While the 2D setting is well suited for analyzing the specific effects of TSN on the tumor cells, it may overestimate the overall efficacy of this compound in the context of a more complex tumor architecture. To the contrary, therapeutic effects of ferroptosis induction may also benefit from secondary effects that are rather underestimated or cannot be monitored by classical 2D cell culture. For example, these include the induction of immunogenic cell death (ICD), based on the conversion of an intrinsic cellular death signal into an extrinsic anti-tumor immune response (26). Ferroptosis may not only induce tumor cell death directly, but also exert an “in situ vaccination” effect, thereby transforming immunologically cold tumors into hot tumors with subsequent immune cell infiltration. Still, barriers to this immune cell infiltration into solid tumors need to be kept in mind (27), since these present a major hurdle as also seen in novel CAR-T cell therapies. Thus, experiments done in more complicated in vitro/ex vivo/in vivo models will be highly relevant. These may include 3D in vitro cell culture (spheroids, organoids), tissue slice and organ-on-a-chip cultures as well as tumor xenograft models, all of which are well-established for various tumor entities (28). Beyond standard GIST cell lines, these studies would also benefit from using primary tumor cells or tumor material, including patient-derived xenograft (PDX) models (29).

Given the mechanisms of ferroptosis induction, it is well feasible that these may circumvent resistance mechanisms associated with apoptosis (30). Thus, it will be particularly interesting to what extent ferroptosis inducers will also show efficacy in resistant cells. While this has not been examined in the paper by Feng et al. (8), it would be definitely worthwhile repeating their experiments in isogenetic cell sub-lines that have been made resistant to classical pharmacological drugs like the above-mentioned Imatinib or Sunitinib by addition of step-wise increasing concentrations of the drug. Beyond this aspect of consecutive treatment, it will also be of major interest to investigate if targeting ferroptosis may provide an additional benefit to single inhibitor treatment like imatinib alone. In the paper Feng et al. (8), these aspects of overcoming or bypassing resistance as well as the possible additive or synergistic effects have not been addressed.

Undoubtedly, TSN may be an interesting drug in addition to other drugs available or under exploration in the context of ferroptosis. These include the first described ferroptosis-inducing compound Erastin that blocks the function of system Xc⁻ (10). Likewise, Sulfasalazine, a well-known anti-inflammatory compound, as well as the multi-kinase inhibitor Sorafenib were identified as ferroptosis inducers by inhibiting system Xc⁻. These are well-established drugs whose discovery as mediators of ferroptosis may lead to novel treatment regimens in the frame of drug repurposing. New compounds have also been developed. These include, e.g., GPX4 inhibitors or degraders, Eprenetapopt (APR-246, acting as a reactivator of mutant p53 and potently depleting cellular GSH) as well as various natural products (16). HDAC inhibitors have been found to be capable of activating lipid peroxidation and ferroptosis in gastric cancer as well (31).

While new small molecule drug candidates may exert attractive effects in cell culture in vitro, limitations have to be considered as well. Generally, these include pharmacokinetic issues like drug biodistribution and bioavailability, pharmacodynamic issues like specificity as well as molecule-inherent properties like solubility or stability. Some of these obstacles may be addressed by using nanocarriers for formulation and improved delivery (32), also by exploring the tumor-associated enhanced permeability and retention (EPR) effect (33).

Beyond this, however, certain nanoparticles may be of particular interest specifically in the context of ferroptosis. Superparamagnetic iron oxide nanoparticles (SPIONs) are well-known as so-called “theranostics” by providing a platform for parallel therapeutic and diagnostic applications (34). In addition to these established roles, their tendency to degrade in the acidic TME is of particular interest here, since this will lead to the release Fe²⁺/Fe³⁺ which can act as catalysts for the above-described Fenton reaction (35). Still, safety issues will have to be considered as well. While iron is an essential trace element, higher systemic levels disrupting iron homeostasis may well lead to toxic side effects in other organs, including liver, kidneys or the CNS (36).

In the field of targeted therapies in cancer, the single action of a specific inhibitor may not be sufficient for achieving a durable response, due to intrinsic or acquired resistance, that is for example based on the presence of salvage pathways or molecular adaptation processes. This may be circumvented by defined combinations of drugs with different mechanisms of action. In this context, the synergistic effect of activating both, ferroptosis and classical apoptosis or newly emerging cell death pathways like cuproptosis (37), is an intriguing approach and should be considered for potentially improving therapeutic efficacy. This, however, will require a deeper understanding of the synergisms of ferroptosis and other cell death forms and their underlying mechanisms. Likewise, synergistic effects of combining ferroptosis induction with radiotherapy, chemotherapy or immunotherapy is a particularly promising concept. In the latter case, ferroptosis may increase efficacies of immune checkpoint inhibitors like programmed cell death 1/programmed death-ligand 1 (PD-1/PD-L1) antibodies (38). The induction of oxidative stress is a key mechanism of radiotherapy (39), which may again be additively or synergistically enhanced by inducers of ferroptosis, thus leading to more extensive damage in tumor cells (40). Interestingly, beyond these combined ROS effects, radiotherapy has also been found to directly increase expression of ferroptosis defence molecules SLC7A11 and GPX4. Thus, their inactivation by ferroptosis inducers can lead to the reversion of an adaptive response to radiotherapy and the re-sensitization of radioresistant cancer cells (41). Chemotherapy often relies on inducing oxidative stress as well, with the tumor cells’ enhanced antioxidative capacity (e.g., based on increased GSH levels or GPX4 expression) representing one mechanism of resistance to cytostatic drugs. Consequently, the combination of cytostatics with inducers of ferroptosis may again lead to improved and more sustained efficacies of chemotherapy (42).

However, clinical translation of ferroptosis induction is still at its early stages, with several preclinical and translational studies needed. Issues and future tasks include the identification of novel ferroptosis-related genes, especially when considering the heterogeneity of GI tumors including GIST, and of novel biomarkers for a reliable identification of patients who will likely respond to specific ferroptosis inducers. Examples for biomarkers are two key genes involved in ferroptosis, SLC7A11 and GPX4, which are indeed often overexpressed in tumors and associated with poor prognosis (16). The role of the non-coding transcriptome, i.e., miRNAs or lncRNAs, should be considered as well. Several miRNAs or lncRNAs are pathologically up- or downregulated in tumors and have already been associated with ferroptosis in various tumor entities including GIST (43).

Current evidence does not demonstrate a direct molecular interaction between KIT and canonical ferroptosis regulators such as GPX4 or SLC7A11. However, KIT inhibition by Imatinib induces oxidative and metabolic stress associated with ferroptosis sensitivity. Moreover, KIT-mutant GIST models, including Imatinib-resistant cells, remain highly sensitive to GPX4 inhibition, while Imatinib itself was shown to induce ferroptosis through STUB1-mediated GPX4 ubiquitination (44,45). Thus, ferroptosis in GIST may represent an indirect consequence of KIT-driven signaling and its therapeutic suppression. Given the central role of KIT in GIST biology, future studies should investigate whether direct mechanistic links between KIT signaling and ferroptosis pathways exist.

In conclusion, additional studies will be necessary to identify reasonable combinations of ferroptosis inducers with other therapies as outlined above. It will be particularly important to assess to what extent the efficacies of existing therapies can be improved upon combination with ferroptosis inducers (42). Beyond the identification of novel compounds for ferroptosis induction or the repurposing of existing drugs, the establishment of nanoscale formulations (nanocarriers) may be of relevance as well. This may also include strategies towards targeted delivery, by introducing targeting moieties on the surface of nanocarriers, for more selective accumulation in the tumor and thus at their desired site of action. While obvious payloads are small molecule drugs, the nanoparticle itself may be of interest when releasing metal ions like iron, or mechanisms of ferroptosis induction may be extended towards nucleic acid-based strategies. In this context, it is well feasible to deliver, e.g., siRNAs for the RNAi-mediated knockdown of ferroptosis- or ROS-inhibiting genes, or CRISPR-Cas based gene editors for more durable effects.

Thus, while ferroptosis offers a rather new mechanism of tumor cell death induction, its therapeutic exploration and translation into the clinics will benefit—and probably require—a broad range of technologies that are nowadays available through other research and development.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0171/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-1-0171/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Gold JS, Gönen M, Gutiérrez A, et al. Development and validation of a prognostic nomogram for recurrence-free survival after complete surgical resection of localised primary gastrointestinal stromal tumour: a retrospective analysis. Lancet Oncol 2009;10:1045-52. [Crossref] [PubMed]
2. Joensuu H, Vehtari A, Riihimäki J, et al. Risk of recurrence of gastrointestinal stromal tumour after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 2012;13:265-74. [Crossref] [PubMed]
3. Heinrich MC, Jones RL, von Mehren M, et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol 2020;21:935-46. [Crossref] [PubMed]
4. Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006;368:1329-38. [Crossref] [PubMed]
5. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:295-302. [Crossref] [PubMed]
6. Blay JY, Serrano C, Heinrich MC, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol 2020;21:923-34. [Crossref] [PubMed]
7. He C, Wang Z, Yu J, et al. Current Drug Resistance Mechanisms and Treatment Options in Gastrointestinal Stromal Tumors: Summary and Update. Curr Treat Options Oncol 2024;25:1390-405. [Crossref] [PubMed]
8. Feng Q, Li Y, Zhong L, et al. Toosendanin induces ferroptosis in gastrointestinal stromal tumor cells through the regulation of the NCOA4 ferritinophagy pathway: implications for tumor proliferation, migration, and invasion. J Gastrointest Oncol 2025;16:853-64. [Crossref] [PubMed]
9. Li S, Xiong Q, Shen Y, et al. Toosendanin: upgrade of an old agent in cancer treatment. Chin J Nat Med 2024;22:887-99. [Crossref] [PubMed]
10. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012;149:1060-72. [Crossref] [PubMed]
11. Bersuker K, Hendricks JM, Li Z, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 2019;575:688-92. [Crossref] [PubMed]
12. Doll S, Freitas FP, Shah R, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 2019;575:693-8. [Crossref] [PubMed]
13. Kraft VAN, Bezjian CT, Pfeiffer S, et al. GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. ACS Cent Sci 2020;6:41-53. [Crossref] [PubMed]
14. Turska-Skrodzka W, Ostrowska A, Krętowski AJ, et al. The functional role of ferroptosis in the development and progression of common cancers. Exp Mol Pathol 2026;146:105050. [Crossref] [PubMed]
15. Fu J, Ren Y, Feng Y, et al. Ferroptosis and cuproptosis in gastric cancer: Mechanisms, roles, and potential Interplay. Int J Biochem Cell Biol 2026;195-196:106942. [Crossref] [PubMed]
16. Zhang Y, Gu Y, Zhan M, et al. Targeting ferroptosis and cuproptosis in gastrointestinal cancers: molecular mechanisms, metabolic vulnerabilities, and therapeutic interventions. Mol Biomed 2025;6:101. [Crossref] [PubMed]
17. Chang S, Zhang M, Liu C, et al. Redox mechanism of glycerophospholipids and relevant targeted therapy in ferroptosis. Cell Death Discov 2025;11:358. [Crossref] [PubMed]
18. Gao M, Yi J, Zhu J, et al. Role of Mitochondria in Ferroptosis. Mol Cell 2019;73:354-363.e3. [Crossref] [PubMed]
19. Oh SJ, Ikeda M, Ide T, et al. Mitochondrial event as an ultimate step in ferroptosis. Cell Death Discov 2022;8:414. [Crossref] [PubMed]
20. Mao C, Liu X, Zhang Y, et al. DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 2021;593:586-90. [Crossref] [PubMed]
21. Yang S, Hu C, Chen X, et al. Crosstalk between metabolism and cell death in tumorigenesis. Mol Cancer 2024;23:71. [Crossref] [PubMed]
22. Jenke R, Heinrich T, Lordick F, et al. ERBB3 influences the ferroptosis pathway via modulation of lipid peroxidation and GSH synthesis in gastric cancer. Cell Death Discov 2025;11:398. [Crossref] [PubMed]
23. Mancias JD, Wang X, Gygi SP, et al. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 2014;509:105-9. [Crossref] [PubMed]
24. Mathias-Machado MC, de Jesus VHF, de Carvalho Oliveira LJ, et al. Current Molecular Profile of Gastrointestinal Stromal Tumors and Systemic Therapeutic Implications. Cancers (Basel) 2022;14:5330. [Crossref] [PubMed]
25. Chantharasamee J, Adashek JJ, Wong K, et al. Translating Knowledge About the Immune Microenvironment of Gastrointestinal Stromal Tumors into Effective Clinical Strategies. Curr Treat Options Oncol 2021;22:9. [Crossref] [PubMed]
26. Zhang X, Tang B, Luo J, et al. Cuproptosis, ferroptosis and PANoptosis in tumor immune microenvironment remodeling and immunotherapy: culprits or new hope. Mol Cancer 2024;23:255. [Crossref] [PubMed]
27. Melssen MM, Sheybani ND, Leick KM, et al. Barriers to immune cell infiltration in tumors. J Immunother Cancer 2023;11:e006401. [Crossref] [PubMed]
28. Sailer V, von Amsberg G, Duensing S, et al. Experimental in vitro, ex vivo and in vivo models in prostate cancer research. Nat Rev Urol 2023;20:158-78. [Crossref] [PubMed]
29. Wang Y, Wozniak A, Wellens J, et al. Plocabulin, a novel tubulin inhibitor, has potent antitumor activity in patient-derived xenograft models of gastrointestinal stromal tumors. Transl Oncol 2020;13:100832. [Crossref] [PubMed]
30. Serrano C, George S. Gastrointestinal Stromal Tumor: Challenges and Opportunities for a New Decade. Clin Cancer Res 2020;26:5078-85. [Crossref] [PubMed]
31. Jenke R, Oliinyk D, Zenz T, et al. HDAC inhibitors activate lipid peroxidation and ferroptosis in gastric cancer. Biochem Pharmacol 2024;225:116257. [Crossref] [PubMed]
32. Ashford M. Drug delivery-the increasing momentum. Drug Deliv Transl Res 2020;10:1888-94. [Crossref] [PubMed]
33. Fang J, Nakamura H, Maeda H. The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 2011;63:136-51. [Crossref] [PubMed]
34. Pawar P, Prabhu A. Smart SPIONs for Multimodal Cancer Theranostics: A Review. Mol Pharm 2025;22:2372-91. [Crossref] [PubMed]
35. Li Y, Wei X, Tao F, et al. The potential application of nanomaterials for ferroptosis-based cancer therapy. Biomed Mater 2021;
36. Yarjanli Z, Ghaedi K, Esmaeili A, et al. Iron oxide nanoparticles may damage to the neural tissue through iron accumulation, oxidative stress, and protein aggregation. BMC Neurosci 2017;18:51. [Crossref] [PubMed]
37. Tsvetkov P, Detappe A, Cai K, et al. Mitochondrial metabolism promotes adaptation to proteotoxic stress. Nat Chem Biol 2019;15:681-9. [Crossref] [PubMed]
38. Wu Y, Zhang K, Jiang N, et al. Iron-fueled ferroptosis: a new axis for immunomodulation to overcome cancer drug resistance-from immune microenvironment crosstalk to therapeutic translation. Front Immunol 2025;16:1726210. [Crossref] [PubMed]
39. Wei W, Ren Y, Lan J, et al. Ionizing radiation: molecular mechanisms, biological effects, and therapeutic targets. Mol Biomed 2026;7:3. [Crossref] [PubMed]
40. Zefrei FJ, Shormij M, Dastranj L, et al. Ferroptosis Inducers as Promising Radiosensitizer Agents in Cancer Radiotherapy. Curr Radiopharm 2024;17:14-29. [Crossref] [PubMed]
41. Lei G, Zhang Y, Koppula P, et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res 2020;30:146-62. [Crossref] [PubMed]
42. Madappan D, Krishnegowda MB, Naik P, et al. Ferroptosis-centered strategies: redefining therapeutic resistance & adaptation in modern oncology. Apoptosis 2026;31:62. [Crossref] [PubMed]
43. Ma Y, Wang Y, Wang S, et al. Regulatory roles of non-coding RNAs in programmed cell death pathways and drug resistance in gastrointestinal stromal tumors. Clin Exp Med 2025;25:150. [Crossref] [PubMed]
44. Sun X, Zhang Q, Lin X, et al. Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination. Cell Death Dis 2023;14:839. [Crossref] [PubMed]
45. Delvaux M, Hagué P, Craciun L, et al. Ferroptosis Induction and YAP Inhibition as New Therapeutic Targets in Gastrointestinal Stromal Tumors (GISTs). Cancers (Basel) 2022;14:5050. [Crossref] [PubMed]