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GPX4-dependent ferroptosis governs ILC2 homeostasis and colitis progression

Cellular & Molecular Immunology volume 23, pages 367–382 (2026)Cite this article

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A Comment to this article was published on 23 March 2026

Abstract

The critical role of group 2 innate lymphoid cells (ILC2s) in host defense and mucosal inflammation has been well established, yet the mechanisms underlying ILC2 survival and death remain unknown. Here, we report that ILC2s are vulnerable to ferroptosis, as evidenced by an abundance of ferroptosis signature genes and the accumulation of lipid peroxidation in ILC2s. Ablation of glutathione peroxidase 4 (GPX4) in ILC2s (Il5Cre/+Gpx4f/f mice) resulted in ferroptosis of ILC2s and diminished their responses. The increase in IFN-γ signaling-enhanced oxidative stress represents the mechanism underlying GPX4 ablation-induced ILC2 ferroptosis. Importantly, Il5Cre/+Gpx4f/f mice exhibited increased susceptibility to DSS-induced colitis. Clinically, ILC2s from inflammatory bowel disease (IBD) patients exhibit reduced GPX4 expression and increased lipid peroxidation. These observations revealed a previously unrecognized role of ferroptosis in ILC2 homeostasis, providing a promising therapeutic opportunity for mucosal inflammatory disorders.

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Data availability

Colonic scRNA-seq data from Il5Cre/+Gpx4f/f and Il5Cre/+Gpx4+/+ immune cells under homeostasis are shown in Figs. 1 and 3 and are openly available from the China National Genomics Data Center (accession number OMIX009034). Bulk RNA-seq data for ILC2s treated with DMSO or RSL3 (Fig. S3) are openly available from the China National Genomics Data Center (accession number OMIX009038).

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Acknowledgements

This work was supported by the following grants: National Key Research and Development Program of China (No. 2025YFA1309100 to JZ), National Natural Science Foundation of China (No. 82525104, 82430055, 82130049 to JZ; 82321001 to YY; and 82225015, 82171284 to QL, 82201917 to GL). This work was also supported by the New Cornerstone Science Foundation through the XPLORER PRIZE (to QL). China Postdoctoral Science Foundation (No. 2022M713571 to GL).

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  1. These authors contributed equally: Gaoyu Liu, Ying Wang, Huachen Huang, Jianye Wang.

Authors and Affiliations

  1. Department of Oncology, Laboratory of Immunity, Inflammation & Cancer, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Gaoyu Liu, Jianye Wang & Jie Zhou

  2. Tianjin Institute of Immunology, Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China

    Gaoyu Liu, Ying Wang, Jianye Wang, Jinhao Yang, Yuxin Zhang, Yuchao Jing, Pan Zhou & Jie Zhou

  3. Division of Hematology/Oncology, Department of Pediatrics, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, China

    Gaoyu Liu & Chun Chen

  4. Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China

    Huachen Huang & Qiang Liu

  5. Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, Tianjin, China

    Jingyi Wu & Hailong Cao

  6. Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China

    Ying Yu

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Contributions

JZ conceived and supervised this study and wrote the manuscript with input from all the authors. QL cosupervised this study. GL, YW, and JW performed most of the experiments. GL analyzed the data and wrote the manuscript. HH analyzed the bioinformatic data. JY, YZ, YJ and PZ participated in the animal experiments. JW and HC collected the samples and clinical information of the IBD patients and paired healthy individuals. YY and CC provided suggestions.

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Correspondence to Qiang Liu or Jie Zhou.

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The authors declare that they have no competing financial interests. JZ is an editorial board member of Cellular & Molecular Immunology; she has not been involved in the peer review or the decision-making of the manuscript.

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Liu, G., Wang, Y., Huang, H. et al. GPX4-dependent ferroptosis governs ILC2 homeostasis and colitis progression. Cell Mol Immunol 23, 367–382 (2026). https://doi.org/10.1038/s41423-026-01388-w

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  • DOI: https://doi.org/10.1038/s41423-026-01388-w

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