The ironclad promise of ferroptosis

By Warren R. Heymann, MD, FAAD
Jan. 25, 2023
Vol. 5, No. 4

As checkpoint inhibition of programmed cell death protein 1 (PD1) has become standard oncologic therapy, it is easy to forget that this revolutionary therapy is barely a decade old. Until 1972, cell death was considered passive and unregulated. Kerr et al proposed the term “apoptosis” (Greek for “apo” = “from” and “ptosis” = fall), describing cells that die as a result of a physiological suicide process rather than because of some catastrophic event (e.g., freezing or burning). (1) The following abstract from Kerr et al is the seminal foundation of modern immune checkpoint inhibitors:

“The term apoptosis is proposed for a hitherto little recognized mechanism of controlled cell deletion, which appears to play a complementary but opposite role to mitosis in the regulation of animal cell populations. Its morphological features suggest that it is an active, inherently programmed phenomenon, and it has been shown that it can be initiated or inhibited by a variety of environmental stimuli, both physiological and pathological.

The structural changes take place in two discrete stages. The first comprises nuclear and cytoplasmic condensation and breaking up of the cell into a number of membrane-bound, ultrastructurally well-preserved fragments. In the second stage these apoptotic bodies are shed from epithelial-lined surfaces or are taken up by other cells, where they undergo a series of changes resembling in vitro autolysis within phagosomes, and are rapidly degraded by lysosomal enzymes derived from the ingesting cells.

Apoptosis seems to be involved in cell turnover in many healthy adult tissues and is responsible for focal elimination of cells during normal embryonic development. It occurs spontaneously in untreated malignant neoplasms, and participates in at least some types of therapeutically induced tumour regression. It is implicated in both physiological involution and atrophy of various tissues and organs. It can also be triggered by noxious agents, both in the embryo and adult animal.”

Subsequent research demonstrated that in addition to apoptosis and necrosis, other new programmed death modes, such as autophagy and necrotic apoptosis, have unique biological processes and pathophysiological characteristics. (3) In 2012, Dixon et al asserted: “Nonapoptotic forms of cell death may facilitate the selective elimination of some tumor cells or be activated in specific pathological states. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of nonapoptotic cell death that we term ferroptosis. Ferroptosis is dependent upon intracellular iron, but not other metals, and is morphologically, biochemically, and genetically distinct from apoptosis, necrosis, and autophagy.” (4)

This commentary will focus on ferroptosis.

Ferroptosis is an iron-dependent cell death accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Morphologically, ferroptosis occurs mainly in cells as reduced mitochondrial volume, increased bilayer membrane density, and reduction or disappearance of mitochondrial cristae. Biochemically, intracellular glutathione (GSH) is depleted; because of decreased activity of glutathione peroxidase 4 (GPX4), lipid peroxides cannot be metabolized by the GPX4-catalyzed reduction reaction, as Fe²⁺ oxidizes lipids. This results in a large amount of ROS, which promotes ferroptosis. Genetically, ferroptosis is regulated by multiple genes affecting iron homeostasis and lipid peroxidation — the specific regulatory mechanism(s) requires further study. Several specific inhibitors of ferroptosis have been identified, including ferrostatin-1, liproxstatin-1 and vitamin E, have been found. (3). As stated by Jiang et al, “…pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation”. (5) According to Gu et al, “...several ferroptosis-targeting drugs have been developed. However, the first-generation ferroptosis-targeting agents remain hampered from clinical use, mainly due to poor selectivity and pharmacokinetics. The discoveries of FSP1, GCH1, and other potential ferroptosis-regulating pathways independent of Xc--GSH-GPX4 provide novel targets for drug design. Recently, protein-targeted degradation and antibody-drug conjugate strategy show promise in future drug design.” (6)

Ferroptosis will become increasingly relevant to dermatologists. Deng et al have identified differentially expressed ferroptosis-related genes (FRGs) and pathways in UVB-induced skin photodamage. (7) FRGs have significant potential for targeted therapies for squamous cell carcinoma chemotherapy resistance. (8) Ferroptosis-related long non-coding RNAs have been demonstrated to accurately predict the prognosis and immune checkpoint inhibitor outcome of melanoma patients. (9) Ferroptosis is involved in autoimmunity; further research may lead to insights in the pathogenesis and treatment of disorders such as lupus and psoriasis. (10, 11)

I recall sitting in the residents’ room in 1980 at Van Etten Hospital in the Bronx (Albert Einstein College of Medicine) when introduced to the concept of apoptosis. I thought it was intriguing but did not have the prescience to predict the future. Honestly, I had never heard of ferroptosis until I read the article by Deng et al (7), but this time, the future is clearer — dermatologists will be very familiar with ferroptosis therapeutically before too long.

Point to Remember: Ferroptosis is a recently discovered form of programmed cell death that is iron-dependent, affecting lipid peroxidation and reactive oxygen species. Modulation of the ferroptosis process will lead to novel therapies in cutaneous oncology and inflammatory disorders.

Our expert’s viewpoint

Brian C. Capell, MD, PhD, FAAD
Assistant Professor of Dermatology and Genetics
Penn Epigenetics Institute / Abramson Cancer Center
University of Pennsylvania Perelman School of Medicine

This article really hits on two of the most exciting aspects of ferroptosis. First, despite having only been really first described a decade ago, there is now growing evidence that it plays a fundamental role in a range of pathological process ranging from tumor suppression and ischemia-reperfusion injury to neurodegeneration and aging. Beyond this however, emerging data suggests that ferroptosis could also play key roles in more physiological and homeostatic processes in the skin such as epidermal cornification and the response to UV. (12,13) For example, those same toxic lipid peroxides that drive ferroptosis, also accumulate in a gradient as epidermal keratinocytes move from more proliferative progenitor cells in the basal layer to more differentiated cells in the stratum granulosum that are about to undergo cornification and cell death. (12) This homeostatic role makes sense given evidence demonstrating ferroptosis to be an evolutionary conserved process across diverse organisms and species, including plants and fungi. (5)

The second reason behind the immense interest in ferroptosis in the biomedical and scientific community (including my own lab) is the ability to modulate ferroptosis with small molecules that may either inhibit or promote the process. Beyond the ability to offer therapeutic benefit on their own, ferroptosis modulators also hold significant potential to potentiate other therapeutic approaches such as immunotherapies, which Dr. Heymann has highlighted here. Indeed, I have no doubt that in just the next few years we will see even more evidence of a key role for ferroptosis in skin homeostasis and disease.

1. Strasser A, Vaux DL. Cell Death in the Origin and Treatment of Cancer. Mol Cell. 2020 Jun 18;78(6):1045-1054. doi: 10.1016/j.molcel.2020.05.014. Epub 2020 Jun 8. PMID: 32516599.

2. Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972 Aug;26(4):239-57. doi: 10.1038/bjc.1972.33. PMID: 4561027; PMCID: PMC2008650.

3. Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, Sun B, Wang G. Ferroptosis: past, present and future. Cell Death Dis. 2020 Feb 3;11(2):88. doi: 10.1038/s41419-020-2298-2. PMID: 32015325; PMCID: PMC6997353.

4. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, Morrison B 3rd, Stockwell BR. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012 May 25;149(5):1060-72. doi: 10.1016/j.cell.2012.03.042. PMID: 22632970; PMCID: PMC3367386.

5. Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021 Apr;22(4):266-282. doi: 10.1038/s41580-020-00324-8. Epub 2021 Jan 25. PMID: 33495651; PMCID: PMC8142022.

6. Gu Y, Li Y, Wang J, Zhang L, Zhang J, Wang Y. Targeting ferroptosis: Paving new roads for drug design and discovery. Eur J Med Chem. 2022 Dec 9;247:115015. doi: 10.1016/j.ejmech.2022.115015. Epub ahead of print. PMID: 36543035.

7. Deng L, Li Y, Wu Q, Zeng Q, He Y, Chen A. Investigating potential ferroptosis-related differentially expressed genes of UVB-induced skin photodamage. Int J Dermatol. 2023 Jan;62(1):79-87. doi: 10.1111/ijd.16472. Epub 2022 Nov 28. PMID: 36440700.

8. Wang J, Xie D, Wu H, Li Y, Wan C. Ferroptosis-related local immune cytolytic activity in tumor microenvironment of basal cell and squamous cell carcinoma. Aging (Albany NY). 2022 May 2;14(9):3956-3972. doi: 10.18632/aging.204057. Epub 2022 May 2. PMID: 35501667; PMCID: PMC9134950.

9. Xu Y, Chen Y, Niu Z, Yang Z, Xing J, Yin X, Guo L, Zhang Q, Yang Y, Han Y. Ferroptosis-related lncRNA signature predicts prognosis and immunotherapy efficacy in cutaneous melanoma. Front Surg. 2022 Jul 21;9:860806. doi: 10.3389/fsurg.2022.860806. PMID: 35937602; PMCID: PMC9354448.

10. Chen Q, Wang J, Xiang M, Wang Y, Zhang Z, Liang J, Xu J. The Potential Role of Ferroptosis in Systemic Lupus Erythematosus. Front Immunol. 2022 Apr 21;13:855622. doi: 10.3389/fimmu.2022.855622. PMID: 35529869; PMCID: PMC9068945.

11. Mao J, Ma X. Bioinformatics Identification of Ferroptosis-Associated Biomarkers and Therapeutic Compounds in Psoriasis. J Oncol. 2022 Oct 12;2022:3818216. doi: 10.1155/2022/3818216. PMID: 36276287; PMCID: PMC9581596.

12. Egolf, S. et al. MLL4 mediates differentiation and tumor suppression through ferroptosis. Sci Adv 7, eabj9141 (2021).

13. Vats, K. et al. Keratinocyte death by ferroptosis initiates skin inflammation after UVB exposure. Redox Biol 47, 102143 (2021).

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