Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

Ferroptosis shapes ILC2 responses in inflammatory bowel disease

Cellular & Molecular Immunology (2026)Cite this article

Subjects

The Original Article was published on 09 February 2026

Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory disorder of the intestine driven by interactions between environmental factors, such as diet, and host genetic susceptibility. Inflamed intestinal tissue exhibits high levels of oxidative stress and is enriched with reactive oxygen species (ROS), increasing the susceptibility of the lipid-rich microenvironment to lipid peroxidation. When unchecked, lipid peroxidation can trigger ferroptosis, a regulated form of cell death driven by oxidative damage to membrane phospholipids [1, 2]. A key protector against ferroptosis is glutathione peroxidase 4 (GPX4), which detoxifies lipid hydroperoxides using glutathione and the selenium-containing amino acid selenocysteine [1]. Although ferroptosis has been extensively studied in epithelial and immune cells, its role in innate lymphoid cell (ILC) homeostasis in IBD remains poorly defined [2]. While ILC1s and ILC3s are well characterized in intestinal inflammation, ILC2 biology in IBD is less understood [3]. A recent study by Liu et al. [4] investigated ferroptosis in ILCs in experimental colitis and human IBD, identifying GPX4 as a critical intrinsic regulator of ferroptosis in ILC2s. The authors propose that GPX4 restrains lipid peroxidation and preserves epithelial barrier integrity during inflammation.

Single-cell RNA sequencing of colonic ILCs revealed that compared with ILC1s and ILC3s, ILC2s display elevated ROS levels and lipid peroxidation even at steady state and express high levels of genes involved in ferroptosis regulation, including Gpx4 and Acsl4. Conditional deletion of GPX4 in IL-5-producing cells in Il5CreGpx4f/f mice markedly reduced the number of colonic ILC2s and decreased the production of IL-5 and IL-13 without affecting proliferation. These findings indicate that GPX4 sustains ILC2 survival and effector function by preventing ferroptotic cell death. The authors reported similar GPX4-dependent control of ILC2 ferroptosis in the lungs during allergic airway inflammation, which is in line with the findings of a recent study [5]. Pharmacologic inhibition of GPX4 with RSL3 during IL-33 stimulation induced ferroptosis and mitochondrial dysfunction in ILC2s, confirming their dependence on GPX4. These observations extend prior work showing that GPX4 inhibits the ferroptosis of ILC3s to support the production of IL-17 and IL-22 during Citrobacter rodentium infection [6]. Notably, Liu et al. reported that, unlike ILC2s, ILC3s were not susceptible to ferroptosis under homeostatic conditions. Whether GPX4-dependent regulation of ILC2 ferroptosis contributes to host defense during bacterial and helminth infections remains unresolved.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1

References

  1. Escuder-Rodriguez JJ, Liang D, Jiang X, Sinicrope FA. Ferroptosis: biology and role in gastrointestinal disease. Gastroenterology. 2024;167:231–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Liu J, Dong R, Yuan B, Xie Y, Feng Z, Zhou S, et al. Immune cells dying from ferroptosis: mechanisms and therapeutic opportunities. Cell Death Dis. 2025;16:878.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sunaga S, Tsunoda J, Teratani T, Mikami Y, Kanai T. Heterogeneity of ILC2s in the intestine; homeostasis and pathology. Front Immunol. 2022;13:867351.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Liu G, Wang Y, Huang H, Wang J, Yang J, Wu J, et al. GPX4-dependent ferroptosis governs ILC2 homeostasis and colitis progression. Cell Mol Immunol. 2026;23:367–82.

    Google Scholar 

  5. Wientjens C, Doverman M, Zurkovic J, More T, Surendar J, Nesic S, et al. Tolerance to ferroptosis facilitates lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation. Immunity. 2026;59:322–38 e329.

    Article  PubMed  CAS  Google Scholar 

  6. Li X, He J, Gao X, Zheng G, Chen C, Chen Y, et al. GPX4 restricts ferroptosis of NKp46(+)ILC3s to control intestinal inflammation. Cell Death Dis. 2024;15:687.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Tsou AM, Yano H, Parkhurst CN, Mahlakoiv T, Chu C, Zhang W, et al. Neuropeptide regulation of nonredundant ILC2 responses at barrier surfaces. Nature. 2022;611:787–93.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Huang W, Zhang Y, Das NK, Solanki S, Jain C, El-Derany MO, et al. Fibroblast lipid metabolism through ACSL4 regulates epithelial sensitivity to ferroptosis in IBD. Nat Metab. 2025;7:1358–74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Liao P, Wang W, Wang W, Kryczek I, Li X, Bian Y, et al. CD8(+) T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell. 2022;40:365–78 e366.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Uddin J, Yano H, Parkhurst CN, Zhang W, Ahmed A, Ribeiro de Godoy V, et al. CGRP-related neuropeptide adrenomedullin 2 promotes tissue-protective ILC2 responses and limits intestinal inflammation. Nat Immunol. 2025;26:1516–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the grants from the National Institutes of Health (NS112263) and Cancer Prevention and Research Institute of Texas (RP220470), USA.

Author information

Authors and Affiliations

  1. Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA

    Anna A. Korchagina & Alexei V. Tumanov

Authors
  1. Anna A. Korchagina
    View author publications

    Search author on:PubMed Google Scholar

  2. Alexei V. Tumanov
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Alexei V. Tumanov.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Korchagina, A.A., Tumanov, A.V. Ferroptosis shapes ILC2 responses in inflammatory bowel disease. Cell Mol Immunol (2026). https://doi.org/10.1038/s41423-026-01404-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41423-026-01404-z

Search

Advanced search

Quick links