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Application prospects of ferroptosis in colorectal cancer

Cancer Cell International volume 25, Article number: 59 (2025) Cite this article

Abstract

Colorectal cancer (CRC) is a serious threat to human health with the third morbidity and the second cancer-related mortality worldwide. It is urgent to explore more effective strategy for CRC because of the acquired treatment resistance from the non-surgical conventional therapies, including radiation, chemotherapy, targeted therapy and immunotherapy. Ferroptosis is a novel form of programmed cell death characterized by iron-dependent lipid peroxidation species (ROS) accumulation and has been identified as a promising target for cancer treatment, especially for those with treatment resistance. In this review, we mainly summarize the recent studies on the influence and regulation of ferroptosis by which (including gut microbiota) modulating the metabolism of iron, amino acid and lipid. Thus this analysis may provide potential targets for inducing CRC ferroptosis and shed lights on the future application of ferroptosis in CRC.

Backgrounds

Colorectal cancer (CRC) has been the third most common malignant tumor all over the world, as well as the second leading cause of cancer-related death [1, 2]. It has shown an obvious increase of morbidity in the past few decades with the changes of dietary structure and lifestyle, especially in young adults [3, 4]. Despite advances in CRC treatment, the effect is not very ideal especially for those with advanced-stage cases because of the treatment resistance developing from non-surgical therapeutics including radiation, chemotherapy, targeted therapy and immunotherapy, etc [5,6,7,8,9,10]. Therefore, it is of great significance to explore new effective treatment for CRC.

Ferroptosis is a newly discovered form of regulated cell death (RCD), which is characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation [11, 12]. And the regulatory mechanism of ferroptosis can be summarized as the abnormal metabolism of iron, amino acid and lipid [13, 14]. Misregulated ferroptosis has been implicated in many pathological processes including the development and treatment of many malignant tumors [15,16,17]. Studies have demonstrated that gut microbiota play pivotal roles in the process of ferroptosis by the generation of carcinogenic metabolites [18,19,20]. Ferroptosis has been reported as the bridge of gut microbiota and many diseases, including CRC [21, 22]. Recent studies have verified that inducing ferroptosis of cancer cells is expected to provide a new strategy for the treatment, especially for those with treatment resistance [23,24,25].

In this review, we mainly summarize the application perspectives of ferroptosis in CRC treatment.

Ferroptosis serves as a promising target for CRC treatment

Studies have demonstrated that ferroptosis is mainly regulated by the metabolism of amino acid, lipid and iron [26]. The dysregulation of them may lead to the misregulation of ferroptosis and result in the occurrence, development, even affect the therapeutic effect of diseases including CRC [27, 28]. So, the readjustment of these metabolic dysregulations may correct the state of ferroptosis and provide potential strategies for CRC treatment. Therefore, ferroptosis may serve as a promising target for CRC treatment. It can be targeted for the CRC treatment mainly via 3 different strategies.

Targeting iron metabolism for CRC treatment by inducing ferroptosis

Iron in our body is mainly derived from food and some derives from the injured erythrocytes. The homeostasis of iron in human cells depends not only on the absorption but also on the storage and efflux of it. Some of the microbial metabolites of gut microbiota, such as glycochenodeoxycholate (GCDC), are demonstrated to increase the absorption of iron; while some other microbial metabolites, such as 1,3-diaminopropane (DAP) and reuterin, are shown to reduce iron absorption [29, 30]. The increased intracellular iron can induce CRC ferroptosis and enhance the sensitivity to the treatment [31].

For example, overexpression of TFRC (Transferrin Receptor), a cell surface receptor necessary for cellular iron uptake, can act with transferrin (TF) and regulate iron metabolism by targeting iron transport [32]. And the action of them can be affected by iron-responsive element-binding protein 2 (IREB2). The direct or indirect change of them can lead to iron transport and eventually the ferroptosis of CRC. For instance, ANXA10 can inhibit CRC ferroptosis by degrading TFRC [33]. MiR-545 was shown to promote CRC cell survival by suppressing transferrin (TF) [34]. MiR-19a could inhibit the ferroptosis of CRC by targeting IREB2 [35]. Also, there are some substances that can influence the uptake or the storage of iron and affect the ferroptosis of CRC, and at last function in CRC treatment. RSL1D1 inhibits ferroptosis by increasing ferritin heavy chain 1 (FTH1) level, which is the major intracellular iron storage protein [36]. Upregulation of heme oxygenase-1 (HO-1) can lead to the increase of iron storage and promote CRC ferroptosis [37]. So, the CRC ferroptosis will be induced by the inhibiting or promoting the expression of the above targets. Therefore, modulating the expression of these molecular targets can induce CRC ferroptosis, and eventually enhance the clinical therapeutic effect of CRC. For example, Tagitinin C can activate HO-1 and induce CRC ferroptosis. Vitamin C (Vit C) can increase the absorption of iron and restrict the emergence of acquired resistance to EGFR-targeted therapies in CRC [38]. Therefore, targeting iron metabolism will be a potential strategy for CRC treatment (Fig. 1).

Fig. 1
figure 1

Targets iron metabolism for CRC treatment by inducing ferroptosis. Iron homeostasis in the body depends on 3 aspects: absorption, storage and efflux of the iron. Regulators of them influence the occurrence of CRC ferroptosis and affect the sensitivity to the treatment

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Targeting amino acid metabolism for CRC treatment by inducing ferroptosis

The cystine/glutamate antiporter system Xc- is an important glutamate transporter. It can import cysteine into cells for glutathione (GSH) production and is a heterodimer consisting of two subunits, solute carrier family 7 membrane 11 (SLC7A11) and solute carrier family 3 membrane 2 (SLC3A2) [39]. GSH synthesized from the amino acids, such as cysteine, has the important antioxidant role in mammals and is also the substrate of glutathione peroxidase 4 (GPX4) [40,41,42]. GPX4 is a selenoprotein, which can protect cells from damage by catalyzing some reactions and thus prevent the occurrence of ferroptosis [43]. Therefore, the abnormality of anyone of them will lead to the misregulation of ferroptosis and affect the therapy.

SLC7A11 is responsible for encoding the xCT subunit of the system Xc − cystine/glutamate antiport and contributes to the cellular defense against oxidative stress by regulating the levels of antioxidant molecules and protecting cells from ferroptosis [44]. Therefore, SLC7A11 can be a potential target for CRC therapy by inducing ferroptosis. It has been reported that miR-148a-3p and miR-509-5p can promote CRC ferroptosis by targeting SLC7A11; while CircRNA circSTIL inhibits CRC ferroptosis via miR-431/SLC7A11 axis [45,46,47]. Some chemical agents, including 2-imino-6-methoxy-2 H-chromene-3-carbothioamide (IMCA, one type of benzopyran derivative), sodium butyrate (SB), Vitamin D (Vit D), Curdione and Erastin (the SLC7A11 inhibitor), can also induce CRC ferroptosis by targeting SLC7A11, too [48,49,50,51]. GPX4 may be another important target for CRC therapy. Gut microbiota play pivotal roles in CRC ferroptosis by regulating GPX4. For example, the increased expression of GPX4 inhibits ferroptosis of colonic tissues and increase the risk of CRC by the function of the gut microbiome metabolite capsiate [52]. Fusobacterium nucleatum induces oxaliplatin resistance by inhibiting ferroptosis through E-cadherin/β-catenin/GPX4 axis in colorectal cancer [53]. There are also some non-coding RNAs, such as miR-15a-3p and miR-539, can induce CRC ferroptosis by downregulating GPX4 expression [49, 54]. Some protein coding gene, such as HSPA5, can repress ferroptosis by maintaining GPX4 at the appropriate level and activity [55]. ACADSB, a member of the acyl-CoA dehydrogenase also has this function [56]. RSL3, a selective ferroptosis inducer, also functions in cancer therapy through regulating the expression of GPX4 [57]. Suppressing the expression of GPX4 enhances the sensitivity of some medicines, such as oxaliplatin, resibufogenin, cetuximab, to CRC by triggering ferroptosis and blocks cellular resistance [58,59,60]. Knocking down SFRS9 expression can also inhibit GPX4 expression and trigger CRC ferroptosis [61].

So, the metabolism of amino acid plays important roles in CRC ferroptosis. Inhibiting the expression of them may provide new therapeutic strategies for combating CRC (Fig. 2).

Fig. 2
figure 2

Targets amino acid metabolism for CRC treatment by inducing ferroptosis. The cysteine/glutamate antiporter system Xc- is an important glutamate transporter which can import cysteine into cells for glutathione (GSH) production. The GSH-GPX4 antioxidation system has an important role in protecting cells from ferroptosis. Regulators of them will lead to the misregulation of ferroptosis and affect the therapy

Full size image

Targeting lipid metabolism for CRC treatment by inducing ferroptosis

Lipids are important molecules that perform structural and functional roles. Lipid peroxidation may lead to increased permeability of the membranes and at last result in the injuries of cells. Polyunsaturated fatty acids (PUFAs) are substrates for the synthesis of lipid signal transduction mediators and have been known to be sensitive to lipid peroxidation and play important roles in regulating ferroptosis [62]. PUFAs can combine with phosphatidylethanolamine (PE) to form phospholipids of polyunsaturated fatty acids (PUFA-PE) under the action of the long chain member of the fatty acyl-CoA synthetase 4 (ACSL4). Thus, reducing the intake of PUFAs or the expression of ACSL4 can decrease the accumulation of lipid peroxide substrates in cells, thereby inhibiting ferroptosis [63, 64].

Studies have revealed that the increase of PUFAs intake plays important roles in the treatment and prevention of CRC by upregulating ferroptosis [65]. The increase of ACSL4-mediated ferroptosis may be helpful for improving treatment effect of CRC [66,67,68,69]. For example, the gut microbiota metabolite glycodeoxycholic acid can promote ACSL4-mediated ferroptosis [29]. CYP1B1 can degrade ACSL4 of CRC and induces anti-PD-1 resistance. CDK1 confers oxaliplatin to CRC by reducing ACSL4 and suppressing ferroptosis. And ACSL4 overexpression can overcome the treatment resistance. Chemical agent such as the apatinib, can promote ferroptosis in CRC cells by upregulating ACSL4, and provide a new application for CRC treatment [69]. Moreover, arachidonate lipoxygenase 3 (ALOXE3), a lipid metabolic gene, will be another target for CRC therapy and the upregulated expression of it can obviously promote ferroptosis of CRC [70]. Furthermore, the gut microbiota modulate host lipid metabolism by targeting the circadian transcription factor NFIL3, which controls the expression of circadian-clock genes [71]. So, targeting the metabolism of lipid may be another therapeutic strategy for CRC (Fig. 3).

Fig. 3
figure 3

Targets lipid metabolism for CRC treatment by inducing ferroptosis. PUFAs are substrates for the synthesis of lipid signal transduction mediators and have been known to be sensitive to lipid peroxidation and play important roles in regulating ferroptosis. PUFAs can combine with PE and to form PUFA-PE under the action of the long chain member of ACSL4. Regulators of them will result in the misregulation of ferroptosis and affect the therapy

Full size image

Additionally, some key genes, such as Nrf2 and p53, are shown to perform essential roles in CRC therapy by inducing ferroptosis through regulating the metabolism of both iron and amino acid or even lipid [72,73,74]. For example, inhibition of Nrf2 can increase the storage of iron and enhance the sensitivity of CRC cells to chemotherapeutic agents by increasing the ROS level and inducing the ferroptosis. In addition, inhibition of Nrf2 can also increase the GSH level and induce CRC ferroptosis. And the knockdown of Nrf2 can also promote lipid peroxidation and suppresses the tumorigenesis of CRC. P53 knockdown increases the sensitivity of CRC cells to RSL3- and erastin-induced ferroptosis by inhibiting YAP1 and ACSL4. Notably, there are also some chemical agents that can affect more than one metabolic pathway. For instance, talaroconvolutin A (TalaA) can induce CRC ferroptosis by not only down-regulating the expression of SLC7A11 (SLC7A11 is a key target of of amino acid metabolism) but also up-regulating ALOXE3 (ALOXE3 is a key molecular of lipid metabolism) [70].

Conclusions

Ferroptosis is the cell death process characterized with increased intracellular iron accumulation and lipid peroxidation and has been one of the hot topics of cancer research in recent years. Although numerous studies have verified the link between ferroptosis and CRC tumorgeneis, progression and therapy, many problems still need to be solved. First, many of the specific molecular mechanisms involved have not been fully interpreted including the specific role of the gut microbiota in regulating ferroptosis. Secondly, the applications of the antitumor activity of related ferroptosis targeted medicines for CRC treatment require further discussion. Therefore, it is necessary to better understand the regulation mechanisms and the application of ferroptosis in CRC, and it will be beneficial for developing more effective ferroptosis targeted medicines.

While immense advancements have been made in understanding the role of ferroptosis in CRC progression and therapy, several challenges still persist. One key area for further elucidation is the specific molecular mechanisms underlying ferroptosis induction. Although increased intracellular iron accumulation and lipid peroxidation are recognized as primary drivers of ferroptosis, the intricate signaling pathways and regulatory networks involved remain not fully understood. Unraveling these mechanisms could provide valuable insights into potential therapeutic targets for CRC. Secondly, despite numerous experimental studies to validate the anticancer efficacy of ferroptosis-targeted therapeutics, there remain significant uncertainties surrounding their clinical implementation in CRC treatment.

Thus, we provide a summary of studies on ferroptosis and the application prospects of ferroptosis in CRC in this review. However, there are still some unresolved questions that need to be further explored.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

ACSL4:

Acyl-CoA synthetase 4

ALOXE3:

Arachidonate lipoxygenase 3

CRC:

Colorectal cancer

FTH1:

Ferritin heavy chain 1

GPX4:

Glutathione peroxidase 4

GSH:

Glutathione

HO-1:

Heme oxygenase-1

PE:

Phosphatidyl ethanolamine

PUFA-PE:

Phospholipids of polyunsaturated fatty acids

PUFAs:

Polyunsaturated fatty acids

RCD:

Regulated cell death

REB2:

Iron-responsive element-binding protein 2

ROS:

Reactive oxygen species

SB:

Sodium butyrate

SLC3A2:

Solute carrier family 3 membrane 2

SLC7A11:

Solute carrier family 7 membrane 11

TalaA:

Talaroconvolutin A

TF:

Transferrin

TFRC:

Transferrin Receptor

Vit C:

Vitamin C

Vit D:

Vitamin D

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Acknowledgements

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Funding

This study was supported by the grants from Henan Province Science and Technology Research Project, the Scientific Research Fund of Xinxiang Medical University and the Scientific Research Fund of the Third Affiliated Hospital of Xinxiang Medical University (212102310145, 505290 and KFKTYB202113).

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Authors and Affiliations

  1. Department of Pathology, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453003, Henan, China

    Gen Yang, Boning Qian, Liya He, Chi Zhang, Jianqiang Wang, Xinlai Qian & Yongxia Wang

  2. Department of Pathology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, 453003, Henan, China

    Xinlai Qian & Yongxia Wang

  3. Henan Provincial Key Laboratory of Molecular Oncologic Pathology, Xinxiang, Henan, China

    Xinlai Qian & Yongxia Wang

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  1. Gen Yang
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  2. Boning Qian
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  3. Liya He
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  4. Chi Zhang
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  6. Xinlai Qian
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Contributions

G.Y. performed literature review and wrote the primary manuscript. Y.X.W., C.Z. and J.Q.W revised the manuscript and designed the figures. X.L.Q provided critical comments on the manuscript. B.N, Q.,L.Y.W. prepared the figures and table. All authors read and approved the manuscript, and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriated investigated and resolved.

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Correspondence to Xinlai Qian or Yongxia Wang.

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Yang, G., Qian, B., He, L. et al. Application prospects of ferroptosis in colorectal cancer. Cancer Cell Int 25, 59 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12935-025-03641-0

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Cancer Cell International

ISSN: 1475-2867

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