Ferroptosis: A New Way to Die


Jacob Schor, ND

Understanding how things die is important for doctors who want to keep their patients alive.   In 1972, the word apoptosis was invented to describe the specific form of cell death in which cells committed suicide in an orderly sequential manner by fissuring into membrane bound apoptotic bodies. At the time this process was the one and only form of programmed cell death scientists were aware of.  Apoptosis has so often been described as ‘programmed cell death,’ since then that the two terms may feel synonymous.1,2 However, apoptosis is now considered just one of a several different types of programmed cell death.  It behooves us to follow these developments closely and understand the different way cells die if we wish to leverage such processes for disease prevention or treatment.

Depending on which source you consult, there are now either three, four, five or as many as ten identified types of programmed cell death.3,4 Probably the best way to organize our thoughts on this matter is an approach suggested in 2018 by Galluzzi and the “Death Nomenclature Committee.”  They divide cell death into two main categories, accidental and regulated depending on activation, whether the process of dying was initiated by a starting signal or not.  In accidental cell death physical or mechanical cell damage leads to cell death whereas in regulated cell death, the event is controlled by molecular or pharmacologic mechanisms.  These regulated deaths can be further categorized into apoptotic or non-apoptotic deaths.  The list of non-apoptotic, but still “programmed cell deaths,” employ the suffix “-ptosis” to signify the programmed nature of the process, for example, pyroptosis, mitoptosis, or ferroptosis.5

The original term ‘apoptosis’ was derived from two Greek words, the prefix “apo-,” translated as “separation,” and the suffix, “-ptosis,” translated as “falling off.” The combined term apoptosis metaphorically references the falling off of leaves from trees in autumn. The new names in which the -ptosis suffix is retained, are still forms of programmed cell death, just not the originally identified process of apoptosis.

That last type of cell death mentioned, ferroptosis, has caught my attention because it may be of relevance to the naturopathic treatment of cancer as well as the prevention of several chronic diseases.  Ferroptosis is the focus of the remainder of this article. 

In this new way to die, the prefix ferro- derives from ferrum, as in iron. It is the chemical reactivity of iron that drives this mechanism of cell death.  Much of what has been discovered about ferroptosis in recent years supports commonly suggested naturopathic therapies, though there are some exceptions where we may want to reconsider some routine practices.

In contrast with apoptosis, which is relatively ‘clean’, ferroptosis is a messy process; it leads to “… a sort of explosive necrotic death able to induce inflammatory response.6 The cells still die in response to dedicated molecular machinery, programmed into cellular DNA that can be induced or prevented through various pharmacological or genetic manipulations—so while still programmed cell death just messier.

That word “recent,” a couple of paragraphs back, could be highlighted as we discuss ferroptosis. The term ‘ferroptosis’ was first used in 2012, not so long ago.  Yet, certain aspects of the process reported many years back went unrecognized. Maybe that word ‘recent’ shouldn’t be there at all. 

Harry Eagle described what we would call ferroptosis in the 1950s as a symptom of cysteine deficiency.7   Without cysteine, cells could not be grown in culture and perished in a distinctive manner.  In 1977, Shiro Bannai linked this type of death by cysteine starvation to glutathione depletion and reactive oxygen species accumulation.8   During the 1960s it was realized that lipid peroxidation reactions were not just a minor problem for cells but a big threat and that these reactions cause significant cellular damage.  By the 1980s these reactions were considered a major repercussion of oxidative damage because they destroyed the lipid structures of cell membranes.

Some of you may recall the excitement for treating cancer with a combination of vitamins K-3 and C to trigger cell death via something called autoschizis.  This occurred in the 1990s following Gilloteaux and Jamison’s descriptions of a peculiar form of tumor cell death caused by glutathione depletion.9 A good guess is that this was an example ferroptosis.

Ferroptosis is now defined as an iron-dependent form of regulated cell death that occurs through accumulation of lipid-based reactive oxygen species (ROS) when glutathione (GSH)-dependent lipid peroxide repair systems have been compromised.10 The mechanisms that drive this suicidal process are distinct and different from apoptosis, necrosis, autophagy, and other forms of cell death. We know that this process is driven by iron’s peroxidation of lipids to produce lethal lipid species because both iron chelators (deferiprone and deferoxamine) or small lipophilic antioxidants (vitamin E) will prevent the process.11,12 Cells undergoing ferroptosis do not exhibit typical apoptotic features (such as chromatin condensation and apoptotic body formation) but are characterized by shrunken mitochondria and reduced numbers of mitochondrial cristae.13

Cells that die from ferroptosis differ in appearance from those dead from apoptosis.  Plasma membranes lose their integrity, the cytoplasm is swollen, the mitochondria are smaller than in normal cells and the mitochondrial cristae shrink or disappear and the outer mitochondrial membranes rupture.  The nuclei remain unchanged without chromatin condensation.14 In fact, the dead cells preserve their distinguishable morphological, biological, and genetic features. This may explain the ferroptosis link to autoimmune disease as the dead cells retain antigenic capability.15

Iron serves as both a catalyst and reactive force to oxidize the polyunsaturated fatty acids (PUFAs) in cell membranes.  Glutathione and the other antioxidants, which would normally halt these reactions, don’t do so. Cell membranes degrade and various autophagy processes are set in motion so that the cell dies.  There are three hallmarks to ferroptosis: Free iron drives the process; phospholipids containing PUFA’s oxidize, and glutathione fails to repair or halt this oxidation.16

While much progress has been made in the last decade to describe the rather complex chemical pathways and interactions that are involved in regulating ferroptosis,17 a great many questions remain regarding how best to use this knowledge to our patients’ advantage.  The more we learn, the less we know.

There are two general and widely different clinical arenas in which to consider the role of ferroptosis.  Ferroptosis plays a role in the development of various vascular and neurodegenerative diseases18 It also plays a role in controlling cancer, which is where my current interest is directed.

The common neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and Huntington’s, are associated with lipid peroxidation and iron. These neurodegenerative diseases are caused by neurons dying from mechanisms involving iron accumulation, lipid peroxidation and cell death by ferroptosis.  The difference in these diseases may only be the location in the brain where the damage occurs and the trigger that initiates the process. Ferroptosis also plays an important role in the development of other diseases, such as acute kidney injury, ischemia/reperfusion injury, autoimmune and cardiovascular disease.19 In a broad sense, if we slow or control ferroptosis, we may also be able to slow or control these diseases.20 This may be done two ways:  chelation of iron or using antioxidants to inhibit ferroptosis.  For example, iron chelation appears to slow both ferroptosis and Parkinson’s disease.21

Ferroptosis may also have an important a role in treating cancer.  But here it is more complex.  Ferroptosis is linked to both promotion and suppression of cancer. In many situations though, “… the distinctive metabolism of cancer cells, their high load of reactive oxygen species (ROS) and their specific mutations render some of them intrinsically susceptible to ferroptosis, thereby exposing vulnerabilities that could be therapeutically targetable in certain cancer types.”  Ferroptosis may enhance cytotoxicity of cancer treatment while at the same time exaggerating adverse reactions to those treatments.

In simple words we might be able to use ferroptosis to kill cancer cells. In the right place with the right cancer, and at the right time, triggering ferroptosis seems desirable.  Many cancer therapies, including radiation, immunotherapy, and targeted therapies work in part by inducing ferroptosis.22 Really, ferroptosis has been used for years to kill cancer but we just weren’t aware of it.  

Tumors seek ways to protect themselves from ferroptosis. Evading ferroptosis leads to tumor growth and development of drug resistance. Finding drugs to prevent this evasion is a hot research topic as it is assumed that triggering ferroptosis or allowing it to go on uninhibited is a strategy for cancer treatment and a target of action for newly developed cancer drugs.

The best known ferroptosis-inducing drug to date is a chemical called erastin.  It acts by impeding the transport system that moves glutathione into cells, inducing a deficiency.  As previously mentioned, cancer cells need glutathione to inhibit ferroptosis. In turn, anything that lowers cysteine levels will limit glutathione production encouraging ferroptosis cell death.

A phase I clinical trial of an analogue of erastin for treating multiple myeloma was listed on Clinical Trials in 2014 but remains unpublished.  This trial was preceded by ex-vivo murine studies that showed a “robust and selective toxicity in a wide variety of tumor cell-lines, and [causes] complete tumor regression in mouse xenograft models of fibrosarcoma, pancreatic cancer, ovarian cancer, colon cancer, and melanoma.”23

Erastin was ‘discovered’ in 2003 during a large screening experiment by Dolma et al.  They were exploring the effect of various compounds on ‘engineered’ cancer cells that overexpressed Small T oncoprotein (ST) and oncogenic RAS. They named the compound they identified as ‘compound eradicator of RAS and ST’ or erastin.24 The cell deaths triggered by erastin were different, lacking the classical apoptotic characteristics and didn’t respond to apoptotic inhibitors. Experiments using erastin were what led to the eventual delineation of ferroptosis.25 Dixon et al named this erastin-induced novel cell death “ferroptosis” in 2012.26

Erastin remains the most thoroughly studied agent to trigger ferroptosis.  It not only induces cells to die, but also sensitizes cancer cells to chemotherapy or radiation. Various analogues of erastin have been developed, though it isn’t always clear in the literature whether this was to enhance functionality or insure patentability. It was an imidazole ketone analogue of erastin that showed beneficial effect on the mice with diffuse large B cell lymphoma in 2019.27

Other drugs that promote or enhance ferroptosis anticancer action28 include acetaminophen (with erastin), auranofin, cisplatin, haloperidol, sorafenib, Sulfasalazine, and neratinib.  Other natural substances that do the same include artemisinin and fenugreek,29,30 piperlongumune,31 ruscogenin, (from Ophiopogon japonicus) in pancreatic cancer cells,32 DHA,33 cordyceps,34 and parthenolide (from feverfew).35,36

Certain substances will prevent ferroptosis from occurring.  N-acetylcysteine (NAC) will, as it supplies cysteine and increases glutathione, putting the brakes on ferroptosis.  Coenzyme Q10 (ubiquinone) will slow ferroptosis because it prevents lipid peroxidation. Polyunsaturated fatty acids oxidize more readily than saturated or monounsaturated fatty acids so increasing PUFAs within cells will increase ferroptosis while increasing monounsaturated or saturated fatty acids will inhibit the process.  Vitamin E and other antioxidant vitamins discourage ferroptosis.

Differences in fat saturation may be important in treatment outcomes.  For example, higher levels of oleic acid offer protection against ferroptosis.37 Such higher levels of oleic acid in the lymph system may be why melanoma cells tend to metastasize via lymph rather than blood. This should draw our attention as oleic acid is predominant in olive oil.  Most people consider olive oil to be good for nearly everything, including cancer. Perhaps it is time to advise melanoma patients to refrain from consuming olive oil and stick with PUFA’s such as fish oil?  The same advice might apply to all cancers that tend toward lymph metastasis. Along with melanoma, that list should include cancers of the breast, gastrointestinal tract, liver, pancreas, lungs, head and neck as well as endocrinological, urological and gynecological cancers.  So pretty much all cancers could be listed. 

This could quickly turn into a debate between advocates of olive oil as a panacea versus those who think the same about fish oil.  The truth probably varies with time and place and what the goal of treatment is. It should be mentioned that a genetic variant that increases uptake of MUFAs into the microenvironment surrounding cancer cells has been linked with shorter overall and relapse-free survival for patients with liver, breast, or ovarian cancers.38

Astragalus may also inhibit ferroptosis, at least it prevents injury to lung tissue by PM2.5 and this protection is thought to be due to ferroptosis inhibition.39 This might be why astragalus protects against cardiotoxicity from doxorubicin.40,41

Perhaps ferroptosis should be encouraged temporarily during treatment with therapies that induce ROS generation to achieve a greater kill rate?  Or perhaps the opposite; maybe we should slightly inhibit ferroptosis during active treatment to reduce collateral damage? Or perhaps we would want to shut down ferroptosis shortly after treatment to lessen adverse effects?

One good argument for encouraging ferroptosis both during and after cancer treatment is the existence of therapy refractory cells, what are called ‘persister cells,’ which although they survived chemo or radiation may still be vulnerable to ferroptosis.42,43

This ferroptosis-encouraging effect of PUFA’s certainly might be seen as an argument in favor of consuming omega-3 fish oils, flaxseed, and other oils susceptible to oxidation. What about giving patients a combination of fish oil with iron to encourage ferroptosis?  This sounds like a good recommendation but as of April 2023, according to Delesderrier et al, we still don’t know: “Scientific evidence still does not allow us to know for sure whether iron and PUFA supplementation are capable of inducing ferroptosis. As the mechanisms that control ferroptosis can determine whether cells proliferate or die, future studies should directly investigate the effects of nutrient supplementation and food intake.”44 It appears that the chemical pathways that regulate this process are complicated.45

There are other drugs besides erastin, and also several natural substances known to encourage ferroptosis.  These drugs, including sorafenib, sulfasalazine, and statins.  Natural substances include artemisinin, withaferin A, fenugreek, and perhaps that autoschizis combination of vitamins C and K-3.  Repurposed drugs are receiving the most attention, especially sorafenib, and particularly with liver cancer.   Ways to enhance sorafenib efficacy relying on ferroptosis include coadministration of iron with the drug,46 treating iron deficiency in drug-resistant cancers,47 laser radiation to increase lipid peroxidation,48 and coadministration with boric acid.49 Withaferin A (from Withania somnifera ) co-administered with sorafenib reduces drug resistance by increasing ferroptosis.50

Sulfasalazine, a drug used in treating ulcerative colitis, impedes cysteine transport into cells and so limits glutathione production.  In doing so it enhances ferroptosis and is being tested to enhance treatment of endometrial cancer.51 Also, by inhibiting cystine transport and inducing ferroptosis, it reduces growth in fibrosarcoma and non-small-cell lung cancer.52 The standard practice of using ionizing radiation to treat cancer induces ferroptosis and this may explain some of its therapeutic benefit.  It may be that small changes in diet or nutritional status during radiation treatment might be leveraged to achieve greater impact.

A comprehensive list of drugs and natural substances that increase ferroptosis is in Ge et al.’s 2022 paper.53 Full text is available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8804219/

Keep in mind that the effect of ferroptosis on cancer isn’t straightforward.  Damage to tissue caused by ferroptosis can trigger inflammation and this can cause immunosuppression in the surrounding tissues and in turn favor tumor growth.  While apoptosis is neat and tidy, ferroptosis is messy and unpredictable; it causes collateral damage.  At the same time ferroptosis induced by radiation helps kill cancer cells, it may add to the damage of healthy tissues, in particular intestinal tissue.54

Several other therapies that are considered helpful in treating cancer including metformin,55 and curcumin,56 also appear to induce ferroptosis. Disulfiram, a drug long used to treat alcoholism, has been repurposed to treat cancer and it too appears to act via ferroptosis.57

On the other hand, several things we might consider for cancer treatment appear to inhibit ferroptosis, including berberine,58 melatonin (in diabetes) [but encourages when used in combination with erastin],59,60 red clover,61 and quercetin.62

Quercetin’s action is complicated; it protects the kidneys in diabetics by inhibiting ferroptosis but in cholangiocarcinoma, it does the opposite, inducing ferroptosis and slowing tumor growth.63

Ferroptosis is helpful some of the time and damaging at others.  It increases effectiveness of cancer therapies but also their unwanted side effects. We may need to flip a coin to decide if we encourage or suppress it.

Ferroptosis is being blamed for progression of atherosclerosis and heart disease.  Resveratrol and ginseng both may offer some protection against these conditions in part because they inhibit ferroptosis.64-66

In theory one might predict exercise would help spur ferroptosis simply because it creates reactive oxygen by increasing energy demands on cell mitochondria.  This sounds good, but no experimental data have been published confirming that exercise does increase ferroptosis.67 There is little doubt though that exercise improves cancer outcomes.

Despite the hundreds of in-vitro studies related to ferroptosis published over the past decade, there is a deficiency of clinical trials listed on PubMed.  The exception may be the trials using C and K-3 to stimulate autoschizis,68 which preceded the adoption of the term ferroptosis and so have not been officially linked to the ‘new cell death’.

We should be cautioned by how little experience anyone has of purposefully inducing or inhibiting ferroptosis in people. Or mice for that matter. We should hesitate before rushing to enhance ferroptosis except in a few specific instances.  While ferroptosis sounds exciting, we don’t even have mice data to extrapolate from.

When might we consider ferroptosis?

  1.  In combination with specific chemotherapy drugs that may result in or have led to drug resistance, for example cisplatin and sorafenib.
  2. In combination with treatments that rely on ferroptosis as their mechanism of action, for example artemisinin treatment, or vitamins C and K-3 treatment.
  3. When considering therapies that may suppress ferroptosis:  iron chelation, antioxidant supplementation, MUFA vs PUFA oil intake. 
  4. With cancers that are classified as epithelial-to-mesenchymal transition.69 Such cancers are apparently more sensitive to ferroptosis.70

How might we gently encourage ferroptosis?

  1. High PUFA intake: fish oil, DHA. \Avoid monounsaturated fats like olive oil.
  2. High iron intake.
  3. Low cysteine intake.  
  4. Exercise

How might we best translate this information in general practice?    Perhaps we need to take a broader view of how biology works, a more philosophical view, one that encompasses the need to allow destruction and cell death to run its course? At least some of the time.  However, in neurodegeneration and cardiovascular disease, the general rule probably should be to discourage ferroptosis.

Reducing ferroptosis might look like high cysteine diets, supplemental cysteine as NAC, and lots of antioxidants, keeping iron status low and consumption of MUFA, (olive oil and low PUFAs).

For treating cancer, we might encourage ferroptosis, by favoring a low cysteine diet, few if any antioxidant supplements, high dietary PUFAs and iron in diet and, and high intensity exercise to increase ROS. And, depending on the situation, radiation therapy, chemotherapy, etc.,..  At least that might be one unproven approach.  The classic vitamin C and vitamin K3 given in a ratio of 100 parts C to 1 part K-3 compounded into a supplement might be considered in addition to these basic dietary measures to deplete glutathione.   Artemisinin might be added to activate the iron and generate ROS.

As I wrote earlier, the more we learn, the less we know, especially when it comes to ferroptosis.

References

  1. Formigli L, Conti A, Lippi D. “Falling leaves”: a survey of the history of apoptosis. Minerva Med. 2004;95(2):159-164.
  2. Fuchs Y, Steller H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat Rev Mol Cell Biol. 2015 Jun;16(6):329-44.
  3. Yan, G., Elbadawi, M., Efferth, T.”Multiple cell death modalities and their key features (Review)”. World Academy of Sciences Journal 2.2 (2020): 39-48
  4. Liu, X., Yang, W., Guan, Z. et al. There are only four basic modes of cell death, although there are many ad-hoc variants adapted to different situations. Cell Biosci 8, 6 (2018). https://doi.org/10.1186/s13578-018-0206-6
  5. Galluzzi L, Vitale I, Aaronson SA, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 2018;25(3):486-541. doi:
  6. Vucetic, M., Daher, B., Cassim, S. et al. Together we stand, apart we fall: how cell-to-cell contact/interplay provides resistance to ferroptosis. Cell Death Dis 11, 789 (2020). https://doi.org/10.1038/s41419-020-02994-w
  7. EAGLE H. The specific amino acid requirements of a human carcinoma cell (Stain HeLa) in tissue culture. J Exp Med. 1955;102(1):37-48.
  8. Bannai, S., Tsukeda, H. & Okumura, H. Effect of antioxidants on cultured human diploid fibroblasts exposed to cystine-free medium. Biochem Biophys. Res Commun. 74, 1582–1588 (1977).
  9. Gilloteaux J, Jamison JM, Arnold D, et al. Cancer cell necrosis by autoschizis: synergism of antitumor activity of vitamin C: vitamin K3 on human bladder carcinoma T24 cells. Scanning. 1998;20(8):564-575.
  10. Stockwell BR, Friedmann Angeli JP, Bayir H, et al. Ferroptosis: A Regulated Cell Death Nexus
  11. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060-1072. 2012.03.042
  12. Yan, Hf., Zou, T., Tuo, Qz. et al. Ferroptosis: mechanisms and links with diseases. Sig Transduct Target Ther 6, 49 (2021).
  13. Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22(7):381-396. 0
  14. Nie Q, Hu Y, Yu X, Li X, Fang X. Induction and application of ferroptosis in cancer therapy. Cancer Cell Int. 2022;22(1):12. Published 2022 Jan 7.
  15. Xie M, Zhu C, Ye Y. Ferroptosis-Related Molecular Clusters and Diagnostic Model in Rheumatoid Arthritis. Int J Mol Sci. 2023;24(8):7342. Published 2023 Apr 16. doi:10.3390/ijms24087342
  16. Sharma A, Flora SJS. Positive and Negative Regulation of Ferroptosis and Its Role in Maintaining Metabolic and Redox Homeostasis. Oxid Med Cell Longev. 2021;2021:9074206. Published 2021 Apr 28.
  17. Tang, D., Chen, X., Kang, R. et al. Ferroptosis: molecular mechanisms and health implications. Cell Res 31, 107–125 (2021).
  18. Sun Y, Xia X, Basnet D, Zheng JC, Huang J, Liu J. Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases. Front Aging Neurosci. 2022;14:904152. Published 2022 Jun 28.
  19. Fan X, Li A, Yan Z, et al. From Iron Metabolism to Ferroptosis: Pathologic Changes in Coronary Heart Disease. Oxid Med Cell Longev. 2022;2022:6291889. Published 2022 Aug 10
  20. Sun Y, Xia X, Basnet D, Zheng JC, Huang J, Liu J. Mechanisms of Ferroptosis and Emerging Links to the Pathology of Neurodegenerative Diseases. Front Aging Neurosci. 2022;14:904152. Published 2022 Jun 28.
  21. Devos D, Moreau C, Devedjian JC, et al. Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal. 2014;21(2):195-210.
  22. Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22(7):381-396.
  23. https://go.drugbank.com/drugs/DB06098
  24. Dolma S, Lessnick SL, Hahn WC, Stockwell BR. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell. 2003;3(3):285-296.
  25. Yagoda N, von Rechenberg M, Zaganjor E, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007;447(7146):864-868.
  26. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060-1072.
  27. Zhang, Y., Tan, H., Daniels, J. D., Zandkarimi, F., Liu, H., Brown, L. M., et al. (2019). Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem. Biol. 26, 623.e29–633.e29.
  28. Zhu J, Xiong Y, Zhang Y, et al. The Molecular Mechanisms of Regulating Oxidative Stress-Induced Ferroptosis and Therapeutic Strategy in Tumors. Oxid Med Cell Longev. 2020 Dec 21;2020:8810785.
  29. Zhu J, Xiong Y, Zhang Y, et al. The Molecular Mechanisms of Regulating Oxidative Stress-Induced Ferroptosis and Therapeutic Strategy in Tumors. Oxid Med Cell Longev. 2020 Dec 21;2020:8810785.
  30. Roh JL, Kim EH, Jang H, Shin D. Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol. 2017;11:254-262.
  31. Yamaguchi Y, Kasukabe T, Kumakura S. Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis. Int J Oncol. 2018;52(3):1011-1022.
  32. Song Z, Xiang X, Li J, et al. Ruscogenin induces ferroptosis in pancreatic cancer cells. Oncol Rep. 2020;43(2):516-524.
  33. Shan K, Feng N, Zhu D, et al. Free docosahexaenoic acid promotes ferroptotic cell death via lipoxygenase dependent and independent pathways in cancer cells. Eur J Nutr. 2022;61(8):4059-4075.
  34. Tomonobu N, Komalasari NLGY, Sumardika IW, et al. Xylitol acts as an anticancer monosaccharide to induce selective cancer death via regulation of the glutathione level. Chem Biol Interact. 2020;324:109085. Full text: https://www.sciencedirect.com/science/article/pii/S0009279720301381?via%3Dihub
  35. LoBianco FV, Krager KJ, Johnson E, et al. Parthenolide induces rapid thiol oxidation that leads to ferroptosis in hepatocellular carcinoma cells. Front Toxicol. 2022;4:936149. Published 2022 Dec 14.
  36. Zhu J, Xiong Y, Zhang Y, et al. The Molecular Mechanisms of Regulating Oxidative Stress-Induced Ferroptosis and Therapeutic Strategy in Tumors. Oxid Med Cell Longev. 2020 Dec 21;2020:8810785. doi: 10.1155/2020/8810785. PMID: 33425217; PMCID: PMC7772020.
  37. Ubellacker JM, Tasdogan A, Ramesh V, et al. Lymph protects metastasizing melanoma cells from ferroptosis. Nature. 2020;585(7823):113-118. doi:10.1038/s41586-020-2623-z
  38. Li Z, Liao X, Hu Y, et al. SLC27A4-mediated selective uptake of mono-unsaturated fatty acids promotes ferroptosis defense in hepatocellular carcinoma [published online ahead of print, 2023 Mar 15]. Free Radic Biol Med. 2023;201:41-54.
  39. Wang X, Wang Y, Huang D, et al. Astragaloside IV regulates the ferroptosis signaling pathway via the Nrf2/SLC7A11/GPX4 axis to inhibit PM2.5-mediated lung injury in mice. Int Immunopharmacol. 2022;112:109186.
  40. Wang W, Zhong X, Fang Z, et al. Cardiac sirtuin1 deficiency exacerbates ferroptosis in doxorubicin-induced cardiac injury through the Nrf2/Keap1 pathway. Chem Biol Interact. 2023;377:110469. doi:10.1016/j.cbi.2023.110469
  41. Li X, Guo X, Li J, Yuan L, Wang H. Preventing effect of astragalus polysaccharide on cardiotoxicity induced by chemotherapy of epirubicin: A pilot study. Medicine (Baltimore). 2022;101(32):e30000. doi:10.1097/MD.0000000000030000
  42. Hangauer MJ, Viswanathan VS, Ryan MJ, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017;551(7679):247-250.
  43. Viswanathan VS, Ryan MJ, Dhruv HD, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547(7664):453-457. d
  44. Delesderrier E, Monteiro JDC, Freitas S, Pinheiro IC, Batista MS, Citelli M. Can Iron and Polyunsaturated Fatty Acid Supplementation Induce Ferroptosis?. Cell Physiol Biochem. 2023;57(S1):24-41.
  45. Lei G, Zhuang L, Gan B. Targeting ferroptosis as a vulnerability in cancer. Nat Rev Cancer. 2022;22(7):381-396.
  46. Liu X, Zhu X, Qi X, Meng X, Xu K. Co-Administration of iRGD with Sorafenib-Loaded Iron-Based Metal-Organic Framework as a Targeted Ferroptosis Agent for Liver Cancer Therapy. Int J Nanomedicine. 2021;16:1037-1050. Published 2021 Feb 11.
  47. Gao Z, Wang D, Yang J, et al. Iron deficiency in hepatocellular carcinoma cells induced sorafenib resistance by upregulating HIF-1α to inhibit apoptosis [published online ahead of print, 2023 Apr 21]. Biomed Pharmacother. 2023;163:114750.
  48. Wang X, Zhao L, Wang C, et al. Potent nanoreactor-mediated ferroptosis-based strategy for the reversal of cancer chemoresistance to Sorafenib. Acta Biomater. 2023;159:237-246.
  49. Corti A, Dominici S, Piaggi S, Pompella A. Enhancement of ferroptosis by boric acid and its potential use as chemosensitizer in anticancer chemotherapy. Biofactors. 2023;49(2):405-414.
  50. Zhang Y, Tan Y, Liu S, et al. Implications of Withaferin A for the metastatic potential and drug resistance in hepatocellular carcinoma cells via Nrf2-mediated EMT and ferroptosis. Toxicol Mech Methods. 2023;33(1):47-55.
  51. Sendo K, Seino M, Ohta T, Nagase S. Impact of the glutathione synthesis pathway on sulfasalazine-treated endometrial cancer. Oncotarget. 2022;13:224-236. Published 2022 Jan 26.
  52. Yin L, Liu P, Jin Y, Ning Z, Yang Y, Gao H. Ferroptosis-related small-molecule compounds in cancer therapy: Strategies and applications. Eur J Med Chem. 2022;244:114861.
  53. Ge C, Zhang S, Mu H, et al. Emerging Mechanisms and Disease Implications of Ferroptosis: Potential Applications of Natural Products. Front Cell Dev Biol. 2022;9:774957. Published 2022 Jan 18. doi:10.3389/fcell.2021.774957
  54. Wang X, Li W, Dong Y, et al. Ferrostatin-1 mitigates ionizing radiation-induced intestinal injuries by inhibiting apoptosis and ferroptosis: an in vitro and in vivo study [published online ahead of print, 2023 Mar 31]. Int J Radiat Biol. 2023;1-12.
  55. Yang J, Zhou Y, Xie S, et al. Metformin induces Ferroptosis by inhibiting UFMylation of SLC7A11 in breast cancer. J Exp Clin Cancer Res. 2021;40(1):206. Published 2021 Jun 23.
  56. Tang X, Ding H, Liang M, et al. Curcumin induces ferroptosis in non-small-cell lung cancer via activating autophagy. Thorac Cancer. 2021 Apr;12(8):1219-1230.
  57. Qiu C, Zhang X, Huang B, et al. Disulfiram, a Ferroptosis Inducer, Triggers Lysosomal Membrane Permeabilization by Up-Regulating ROS in Glioblastoma. Onco Targets Ther. 2020;13:10631-10640. Published 2020 Oct 20.
  58. Yang KT, Chao TH, Wang IC, Luo YP, Ting PC, Lin JH, Chang JC. Berberine protects cardiac cells against ferroptosis. Tzu Chi Med J. 2022 Mar 4;34(3):310-317.
  59. Ma H, Wang X, Zhang W, et al. Melatonin Suppresses Ferroptosis Induced by High Glucose via Activation of the Nrf2/HO-1 Signaling Pathway in Type 2 Diabetic Osteoporosis. Oxid Med Cell Longev. 2020;2020:9067610.
  60. Wang L, Wang C, Li X, et al. Melatonin and erastin emerge synergistic anti-tumor effects on oral squamous cell carcinoma by inducing apoptosis, ferroptosis, and inhibiting autophagy through promoting ROS. Cell Mol Biol Lett. 2023;28(1):36.
  61. Won JP, Kim E, Hur J, Lee HG, Lee WJ, Seo HG. Red clover (Trifolium pratense L.) extract inhibits ferroptotic cell death by modulating cellular iron homeostasis. J Ethnopharmacol. 2023;308:116267.
  62. Feng Q, Yang Y, Qiao Y, et al. Quercetin Ameliorates Diabetic Kidney Injury by Inhibiting Ferroptosis via Activating Nrf2/HO-1 Signaling Pathway [published online ahead of print, 2023 Apr 10]. Am J Chin Med. 2023;1-22.
  63. Song Y, Zhang Z, Chai Q, et al. Quercetin Inhibits Intrahepatic Cholangiocarcinoma by Inducing Ferroptosis and Inhibiting Invasion via the NF-B Pathway Am J Chin Med. 2023;1-21.
  64. Zeng Y, Cao G, Lin L, et al. Resveratrol Attenuates Sepsis-Induced Cardiomyopathy in Rats through Anti-Ferroptosis via the Sirt1/Nrf2 Pathway. J Invest Surg. 2023;36(1):2157521.
  65. Ye J, Lyu TJ, Li LY, et al. Ginsenoside Re attenuates myocardial ischemia/reperfusion induced ferroptosis via miR-144-3p/SLC7A11. Phytomedicine. 2023;113:154681.
  66. Chen X, Kang R, Kroemer G, Tang D. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol. 2021;18(5):280-296.
  67. Soh J, Lim ZX, Lim EH, Kennedy BK, Goh J. Ironing out exercise on immuno-oncological outcomes. J Immunother Cancer. 2022;10(9):e002976.
  68. Tareen B, Summers JL, Jamison JM, et al. A 12 week, open label, phase I/IIa study using apatone for the treatment of prostate cancer patients who have failed standard therapy. Int J Med Sci. 2008 Mar 24;5(2):62-7.
  69. Nieto MA. The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol. 2011;27:347-376.
  70. Roche J. The Epithelial-to-Mesenchymal Transition in Cancer. Cancers (Basel). 2018 Feb 16;10(2):52.

Published March 23, 2024

About the Author

Jacob Schor, ND, now retired, had a general practice with a focus on naturopathic oncology in Denver, Colorado. He served as Abstract & Commentary Editor for the Natural Medicine Journal for several years (https://www.naturalmedicinejournal.com/) and posts blog articles on natural therapies,  nutrition, and cancer (https://drjacobschor.wordpress.com/). He was a board member of CoAND and past president of OncANP, and is someone who is happier outdoors than inside.