Ferroptosis

Overview

Ferroptosis is a regulated (programmed) cell-death process caused by iron-dependent peroxidation of membrane phospholipids. It was coined in 2012 to describe a non-apoptotic death pathway triggered by disrupting cystine uptake and cellular antioxidant capacity, and inhibited by lipophilic “radical-trapping” compounds such as ferrostatin‑1.^[1][2] Ferroptosis is distinct from apoptosis and necroptosis because the lethal lesion is not DNA cleavage or a dedicated pore-forming executioner protein; instead, the cell crosses a biochemical threshold at which oxidized polyunsaturated lipids accumulate faster than they can be detoxified or replaced, leading to catastrophic loss of membrane integrity and ionic homeostasis.^[3]

Key regulators and practical handles on ferroptosis

Pathway node	What it controls	Representative genes/proteins	Typical implications (biology & translational)
PUFA-phospholipid loading	Size of oxidizable membrane lipid pool	ACSL4, LPCAT3 (context-dependent)	Higher PUFA‑PL content often increases vulnerability; lipid remodeling is a frequent cancer and immune-activation adaptation.[4][5]
Iron handling	Labile iron availability for lipid radical propagation	TFRC, ferritin; iron export/import regulators	Iron accumulation can sensitize neurons, kidney tubules, and tumors; iron chelation is a common specificity control in models.[6]
Cystine/GSH supply	Reducing equivalents for lipid repair	System x_c− (SLC7A11), GSH metabolism	Cystine starvation and GSH depletion are classic ferroptosis entry points; relevant in ischemia–reperfusion and some tumors.[7]
Lipid hydroperoxide detoxification	Direct repair of peroxidized phospholipids	GPX4 (selenoprotein)	Central developmental and immune checkpoint; GPX4 inhibition is an anticancer concept but may impair immune effector cells.[8]
GPX4-independent buffering	Membrane radical trapping / CoQ recycling	FSP1 (AIFM2)–CoQ10	Helps explain resistance; can be engaged by tumor and microbe-derived pathways.[9]

Common hallmarks and how ferroptosis is identified

In practice, ferroptosis is typically inferred from a pattern of biochemical features rather than a single marker. Common hallmarks used in research include increased lipid peroxidation (often measured with lipid ROS probes such as C11‑BODIPY or by lipid peroxidation end-products), dependence on iron (partial rescue by iron chelators), and rescue by lipophilic radical‑trapping antioxidants such as ferrostatin‑1 or liproxstatin‑1.^[10][11][12] Supportive evidence can include GSH depletion, reduced GPX4 activity, and transcriptional/metabolic states that increase PUFA‑phospholipids or labile iron. Because other death programs can co-occur under severe stress, best practice is to use multiple orthogonal readouts and demonstrate pharmacologic or genetic “rescue” consistent with ferroptosis rather than relying on morphology or a single oxidative stress marker.^[13]

Importance in development and tissue homeostasis

Ferroptosis matters in development because it ties cell survival to lipid redox control during rapid membrane remodeling. The strongest genetic signal comes from GPX4 biology: GPx4 deficiency causes abnormal embryonic development and lethality in mice, and conditional knockout models demonstrate profound tissue vulnerability consistent with ferroptotic injury when lipid peroxide repair is removed.^[14] Developmental and homeostatic phenotypes appear most strongly in lineages that combine high membrane lipid flux, high oxidative burden, or limited antioxidant reserve. Examples include erythropoiesis, where GPX4 is implicated in human erythroblast enucleation, linking lipid-peroxide control to red cell maturation.^[15] Conditional Gpx4 ablation in adult neurons can produce rapid degeneration, illustrating how ferroptosis suppression becomes indispensable in specific neural compartments.^[16] Since GPX4 is selenium-containing, selenium availability can tune ferroptosis resistance in vivo, adding a nutritional layer to developmental and tissue resilience.^[17]

Ferroptosis in immunity

Immune activation reshapes iron trafficking, ROS production, and membrane lipid metabolism, precisely the terrain that determines ferroptosis sensitivity. Consequently, ferroptosis functions as a metabolic checkpoint for immune cell fitness. A well-defined example is the selenium–GPX4 axis in T cells. A paper in Nature Immunology shows GPX4 protects T follicular helper (Tfh) cells from ferroptosis, and selenium supplementation increased GPX4 expression and boosted antibody responses in the studied settings.^[18] Ferroptosis is also directly relevant to immunotherapy manufacturing and performance. A 2025 open-access study reports that stimulation rewires T-cell redox/iron balance, that GPX4 acts as a master regulator of T/CAR‑T sensitivity to ferroptosis, and that GPX4 inhibition impaired CAR‑T antitumor function—highlighting a key tradeoff: inducing ferroptosis to kill tumors may simultaneously weaken immune effectors.^[19][20] More broadly, reviews emphasize extensive crosstalk between ferroptosis programs and immune signaling in cancer.^[21]

Importance in major diseases

Cancer

Ferroptosis is studied as an anticancer strategy because many tumors operate under chronic oxidative and metabolic stress and rely on ferroptosis-suppressing pathways (e.g., cystine uptake, GPX4, CoQ-based defenses) for survival. The original ferroptosis study already proposed exploiting this vulnerability, including in oncogene-driven contexts.^[22] However, the immunology section’s caveat is crucial: ferroptosis induction in tumors must be balanced against potential ferroptosis in immune cells, especially for combination regimens with immunotherapies.^[23][24]

Neurodegeneration

Neurons are vulnerable to ferroptosis because of oxidizable lipid-rich membranes and sensitivity to iron dysregulation. Reviews link ferroptosis-like mechanisms to Alzheimer’s and Parkinson’s disease and related neurodegenerative disorders.^[25][26] A particularly strong causal datapoint is a 2026 open-access Cell paper describing a neurodegeneration-associated GPX4 variant (R152H) that increases ferroptotic vulnerability in patient-derived neurons and organoids and drives neurodegeneration with Alzheimer’s-like signatures in mouse models.^[27]

Stroke

Ischemia–reperfusion creates ferroptosis-permissive conditions: ROS surges, iron dysregulation, and glutathione depletion. Recent reviews summarize ferroptosis involvement in ischemic stroke and discuss therapeutic strategies including iron chelation and ferroptosis inhibitors.^[28][29]

Kidney injury

Acute kidney injury (AKI), particularly ischemia–reperfusion injury, is increasingly linked to ferroptosis in renal tubular cells. Reviews report protective effects of ferroptosis inhibitors such as liproxstatin‑1 and note that liproxstatin‑1 delayed lethal AKI in GPX4 knockout mice; ferroptosis is implicated across multiple AKI models (ischemia–reperfusion, cisplatin toxicity, crystal nephropathy).^[30][31]

Microbiome connections

The gut microbiome can plausibly modulate ferroptosis by changing host iron availability, lipid metabolism, antioxidant tone, and inflammation. A 2024 review frames ferroptosis as a potential bridge linking gut microbiota and chronic kidney disease, discussing how dysbiosis and microbial metabolites might influence lipid/iron pathways and oxidative stress while emphasizing that causal human evidence is still emerging.^[32] In cancer, a clear mechanistic example is highlighted in a Nature Cell Biology News & Views: a study links the microbial tryptophan metabolite trans‑3‑indoleacrylic acid (IDA) from Peptostreptococcus anaerobius to colorectal carcinogenesis through an AHR–ALDH1A3–FSP1–CoQ10 axis, directly tying a microbiome-derived metabolite to a canonical ferroptosis defense pathway.^[33][34]

Microbiome-related element	Mechanism
Iron competition and iron-binding strategies	Gut microbes compete for iron and can shift host iron handling; changes in iron availability affect the labile iron pool, which can accelerate lipid peroxidation chemistry that drives ferroptosis. This is commonly discussed as one route by which dysbiosis may alter oxidative injury risk in systemic disease contexts (e.g., CKD).[35]
Tryptophan metabolites (indole family)	Indole derivatives can signal through host receptors (notably AHR) and reprogram redox and lipid-defense pathways. In CRC, microbial IDA has been tied to ferroptosis suppression via AHR–ALDH1A3–FSP1–CoQ10, increasing resistance to lipid radical damage.[36][37]
Short-chain fatty acids (SCFAs: acetate/propionate/butyrate)	SCFAs can modify inflammation and oxidative stress programs and, in some models, shift expression of ferroptosis-related genes and sensitivity to ferroptosis triggers. A 2024 experimental study shows SCFAs can regulate erastin-induced ferroptosis and ferroptosis gene programs in cardiomyocytes.[38][39]
Bile acid metabolism (primary ↔ secondary bile acids)	Microbes transform bile acids, which act as signaling molecules that can reshape lipid metabolism, mitochondrial function, and inflammatory tone, factors that can indirectly tune membrane peroxidation susceptibility and antioxidant capacity. Reviews in intestinal disease contexts highlight bile acids among key microbial metabolite classes linked to ferroptosis regulation.[40][41]
Microbiome-driven changes in membrane lipid composition	Diet–microbiome interactions can alter host lipid pools (availability of PUFAs vs MUFAs, phospholipid remodeling), changing how “peroxidizable” membranes are an upstream determinant of ferroptosis susceptibility. CRC-focused reviews explicitly describe microbial metabolites influencing ferroptosis sensitivity via metabolic remodeling.[42]

Research Feed

Update History

References

1. Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death.. Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., Morrison, B., & Stockwell, B. R. (2012).. (Cell, 149(5), 1060-1072.)
2. Ferroptosis: principles and significance in health and disease.. Chen, F., Kang, R., Tang, D. et al.. (J Hematol Oncol 17, 41 (2024).)
3. Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease.. Stockwell, B. R., Friedmann Angeli, J. P., Bayir, H., Bush, A. I., Conrad, M., Dixon, S. J., Fulda, S., Gascón, S., Hatzios, S. K., Kagan, V. E., Noel, K., Jiang, X., Linkermann, A., Murphy, M. E., Overholtzer, M., Oyagi, A., Pagnussat, G. C., Park, J., Ran, Q., . . . Zhang, D. D. (2017).. (Cell, 171(2), 273-285.)
4. Targeting ACSLs to modulate ferroptosis and cancer immunity.. Lin J, Lai Y, Lu F, Wang W.. (Trends Endocrinol Metab. 2025 Jul;36(7):677-690.)
5. Lipid metabolism in ferroptosis: Mechanistic insights and therapeutic potential.. Sun, D., Wang, L., Wu, Y., Yu, Y., Yao, Y., Yang, H., & Hao, C. (2025).. (Frontiers in Immunology, 16, 1545339.)
6. The biology of ferroptosis in kidney disease.. Seibt, T., Wahida, A., Hoeft, K., Kemmner, S., Linkermann, A., Mishima, E., & Conrad, M. (2024).. (Nephrology Dialysis Transplantation, 39(11), 1754-1761.)
7. Ferroptosis in ischemic stroke: Mechanisms, pathological implications, and therapeutic strategies.. Long, Z., Zhu, Y., Zhao, H., Liao, S., & Liu, C. (2025).. (Frontiers in Neuroscience, 19, 1623485.)
8. Regulation of Ferroptotic Cancer Cell Death by GPX4.. Yang, W. S., SriRamaratnam, R., Welsch, M. E., Shimada, K., Skouta, R., Viswanathan, V. S., Cheah, J. H., Clemons, P. A., Shamji, A. F., Clish, C. B., Brown, L. M., Girotti, A. W., Cornish, V. W., Schreiber, S. L., & Stockwell, B. R. (2014).. (Cell, 156, 317.)
9. Microbial regulation of ferroptosis in cancer.. Zhang, Q., Goswami, S. & Yilmaz, O.. (Nat Cell Biol 26, 41–42 (2024).)
10. Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death.. Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., Morrison, B., & Stockwell, B. R. (2012).. (Cell, 149(5), 1060-1072.)
11. Beyond ferrostatin-1: A comprehensive review of ferroptosis inhibitors.. Scarpellini, C., Klejborowska, G., Lanthier, C., Hassannia, B., Vanden Berghe, T., & Augustyns, K. (2023).. (Trends in Pharmacological Sciences, 44(12), 902-916.)
12. The biology of ferroptosis in kidney disease.. Seibt, T., Wahida, A., Hoeft, K., Kemmner, S., Linkermann, A., Mishima, E., & Conrad, M. (2024).. (Nephrology Dialysis Transplantation, 39(11), 1754-1761.)
13. Beyond ferrostatin-1: A comprehensive review of ferroptosis inhibitors.. Scarpellini, C., Klejborowska, G., Lanthier, C., Hassannia, B., Vanden Berghe, T., & Augustyns, K. (2023).. (Trends in Pharmacological Sciences, 44(12), 902-916.)
14. GPX4 in cell death, autophagy, and disease.. Xie, Y., Kang, R., Klionsky, D. J., & Tang, D. (2023).. (Autophagy, 19(10), 2621–2638.)
15. A new role of glutathione peroxidase 4 during human erythroblast enucleation.. Hakim Ouled-Haddou, Kahia Messaoudi, Yohann Demont, Rogiéro Lopes dos Santos, Candice Carola, Alexis Caulier, Pascal Vong, Nicolas Jankovsky, Delphine Lebon, Alexandre Willaume, Julien Demagny, Thomas Boyer, Jean-Pierre Marolleau, Jacques Rochette, Loïc Garçon;. (Blood Adv 2020; 4 (22): 5666–5680.)
16. Ablation of the Ferroptosis Inhibitor Glutathione Peroxidase 4 in Neurons Results in Rapid Motor Neuron Degeneration and Paralysis.. Chen, L., Hambright, W. S., Na, R., & Ran, Q. (2015).. (Journal of Biological Chemistry, 290(47), 28097-28106.)
17. Selenium: Tracing Another Essential Element of Ferroptotic Cell Death.. Conrad M, Proneth B.. (Cell Chem Biol. 2020 Apr 16;27(4):409-419.)
18. Selenium–GPX4 axis protects follicular helper T cells from ferroptosis.. Yao, Y., Chen, Z., Zhang, H., Chen, C., Zeng, M., Yunis, J., Wei, Y., Wan, Y., Wang, N., Zhou, M., Qiu, C., Zeng, Q., Ong, H. S., Wang, H., Makota, F. V., Yang, Y., Yang, Z., Wang, N., Deng, J., . . . Yu, D. (2021).. (Nature Immunology, 22(9), 1127-1139.)
19. Ferroptosis in immune cells: Implications for tumor immunity and cancer therapy.. Gao, J., Zhang, X., Liu, Y., & Gu, X. (2025).. (Cytokine & Growth Factor Reviews, 84, 59-73.)
20. GPX4 is a key ferroptosis regulator orchestrating T cells and CAR-T-cells sensitivity to ferroptosis.. Kłopotowska, M., Baranowska, I., Hajduk, S. et al.. (Cancer Immunol Immunother 74, 280 (2025).)
21. Ferroptosis in immune cells: Implications for tumor immunity and cancer therapy.. Gao, J., Zhang, X., Liu, Y., & Gu, X. (2025).. (Cytokine & Growth Factor Reviews, 84, 59-73.)
22. Ferroptosis: An Iron-Dependent Form of Nonapoptotic Cell Death.. Dixon, S. J., Lemberg, K. M., Lamprecht, M. R., Skouta, R., Zaitsev, E. M., Gleason, C. E., Patel, D. N., Bauer, A. J., Cantley, A. M., Yang, W. S., Morrison, B., & Stockwell, B. R. (2012).. (Cell, 149(5), 1060-1072.)
23. GPX4 is a key ferroptosis regulator orchestrating T cells and CAR-T-cells sensitivity to ferroptosis.. Kłopotowska, M., Baranowska, I., Hajduk, S. et al.. (Cancer Immunol Immunother 74, 280 (2025).)
24. Ferroptosis in immune cells: Implications for tumor immunity and cancer therapy.. Gao, J., Zhang, X., Liu, Y., & Gu, X. (2025).. (Cytokine & Growth Factor Reviews, 84, 59-73.)
25. A critical appraisal of ferroptosis in Alzheimer’s and Parkinson’s disease: New insights into emerging mechanisms and therapeutic targets.. Soni, P., Ammal Kaidery, N., Sharma, S. M., Gazaryan, I., Nikulin, S. V., Hushpulian, D. M., & Thomas, B. (2024).. (Frontiers in Pharmacology, 15, 1390798.)
26. Ferroptosis as a mechanism of neurodegeneration in Alzheimer's disease.. Jakaria, M., Belaidi, A. A., Bush, A. I., & Ayton, S. (2021).. (Journal of Neurochemistry, 159(5), 804-825.)
27. A fin-loop-like structure in GPX4 underlies neuroprotection from ferroptosis.. Lorenz, S. M., Wahida, A., Bostock, M. J., Seibt, T., Santos Dias Mourão, A., Levkina, A., Trümbach, D., Soudy, M., Emler, D., Rothammer, N., Woo, M. S., Sonner, J. K., Novikova, M., Henkelmann, B., Aldrovandi, M., Kaemena, D. F., Mishima, E., Vermonden, P., Zong, Z., . . . Conrad, M. (2026).. (Cell, 189(1), 287-306.e35.)
28. Ferroptosis in ischemic stroke: Mechanisms, pathological implications, and therapeutic strategies.. Long, Z., Zhu, Y., Zhao, H., Liao, S., & Liu, C. (2025).. (Frontiers in Neuroscience, 19, 1623485.)
29. Inhibiting ferroptosis: A novel approach for stroke therapeutics.. Jin, Y., Zhuang, Y., Liu, M., Che, J., & Dong, X. (2021).. (Drug Discovery Today, 26(4), 916-930.)
30. The biology of ferroptosis in kidney disease.. Seibt, T., Wahida, A., Hoeft, K., Kemmner, S., Linkermann, A., Mishima, E., & Conrad, M. (2024).. (Nephrology Dialysis Transplantation, 39(11), 1754-1761.)
31. Ferroptosis and Acute Kidney Injury (AKI): Molecular Mechanisms and Therapeutic Potentials.. Feng, Q., Yu, X., Qiao, Y., Pan, S., Wang, R., Zheng, B., Wang, H., Ren, K., Liu, H., & Yang, Y. (2022).. (Frontiers in Pharmacology, 13, 858676.)
32. Ferroptosis: A potential bridge linking gut microbiota and chronic kidney disease.. Mao, Z., Gao, Z., Pan, S., Liu, D., Liu, Z., & Wu, P. (2024).. (Cell Death Discovery, 10(1), 234.)
33. Microbial regulation of ferroptosis in cancer.. Zhang, Q., Goswami, S. & Yilmaz, O.. (Nat Cell Biol 26, 41–42 (2024).)
34. Gut Microbiome Mediates Ferroptosis Resistance for Colorectal Cancer Development.. Ruoxi Zhang, Rui Kang, Daolin Tang;. (Cancer Res 15 March 2024; 84 (6): 796–797.)
35. Ferroptosis: A potential bridge linking gut microbiota and chronic kidney disease.. Mao, Z., Gao, Z., Pan, S., Liu, D., Liu, Z., & Wu, P. (2024).. (Cell Death Discovery, 10(1), 234.)
36. Microbial regulation of ferroptosis in cancer.. Zhang, Q., Goswami, S. & Yilmaz, O.. (Nat Cell Biol 26, 41–42 (2024).)
37. Gut Microbiome Mediates Ferroptosis Resistance for Colorectal Cancer Development.. Ruoxi Zhang, Rui Kang, Daolin Tang;. (Cancer Res 15 March 2024; 84 (6): 796–797.)
38. Short-chain fatty acids regulate erastin-induced cardiomyocyte ferroptosis and ferroptosis-related genes.. He, X., Long, Q., Zhong, Y., Zhang, Y., Qian, B., Huang, S., Chang, L., Qi, Z., Li, L., Wang, X., Yang, X., Dong Gao, W., Ye, X., & Zhao, Q. (2024).. (Frontiers in Pharmacology, 15, 1409321.)
39. The metabolites of gut microbiota: their role in ferroptosis in inflammatory bowel disease.. Zhou, J., Lu, P., He, H. et al.. (Eur J Med Res 30, 248 (2025).)
40. The metabolites of gut microbiota: their role in ferroptosis in inflammatory bowel disease.. Zhou, J., Lu, P., He, H. et al.. (Eur J Med Res 30, 248 (2025).)
41. Gut microbial metabolism in ferroptosis and colorectal cancer.. Cui, W., Hao, M., Yang, X., Yin, C., & Chu, B. (2025).. (Trends in Cell Biology, 35(4), 341-351.)
42. Gut microbial metabolism in ferroptosis and colorectal cancer.. Cui, W., Hao, M., Yang, X., Yin, C., & Chu, B. (2025).. (Trends in Cell Biology, 35(4), 341-351.)