{
  "abstract": "Regulatory T cells (Tregs) hold great promise as next-generation therapeutics for autoimmune diseases. However, maintaining their functional persistence within inflamed tissues remains a major translational challenge. Using an in vitro system that recapitulates the inflammatory CNS milieu of multiple sclerosis (MS), together with a pooled shRNA screen, we identify necroptotic signaling as a key driver of Treg death, thereby compromising Treg functional persistence under inflammatory conditions. We further demonstrate that Tregs in both a mouse model of MS and patients with MS exhibited a preferential susceptibility to receptor-interacting serine/threonine kinase 1–dependent (RIPK1-dependent) necroptosis. Mechanistically, a FOXP3-driven, low-glucose metabolic program rendered Tregs intrinsically susceptible to necroptosis by limiting O-GlcNAcylation (O-GlcNAc) modification on RIPK1. This vulnerability was not shared by conventional T cells under comparable inflammatory conditions. Finally, in combination with adoptive Treg transfer, we show that selective inhibition of necroptosis in Tregs enhanced their survival and suppressive function at sites of active inflammation, thereby reducing autoimmune pathology in mouse models of MS and systemic lupus erythematosus. Together, these findings identify necroptotic cell death as a barrier to Treg persistence within inflamed tissues and highlight the therapeutic potential of necroptosis-resistant Tregs for the treatment of autoimmune diseases.",
  "abstract_shown": true,
  "affiliations": [
    "Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China.",
    "University of Chinese Academy of Sciences, Beijing, China.",
    "Department of Neurology, and",
    "Department of Anesthesiology, Key Laboratory of the Ministry of Education, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.",
    "Clinical Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.",
    "Shanghai Key Laboratory of Aging Studies, Shanghai, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Qiaoyan Wu"
    },
    {
      "affs": [
        0
      ],
      "name": "Na Cui"
    },
    {
      "affs": [
        2
      ],
      "name": "Li Gao"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Zhihui Lu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xiang Ao"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Rui Pang"
    },
    {
      "affs": [
        0
      ],
      "name": "Xingyan Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Heling Pan"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Daichao Xu"
    },
    {
      "affs": [
        3,
        4
      ],
      "name": "Peiying Li"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Junying Yuan"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Chengyu Zou"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fp14888k226hf.bib",
  "cited_by": 0,
  "doi": "10.1172/jci207077",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13722395/",
  "id": "fp14888k226hf",
  "issns": [
    "0021-9738",
    "1558-8238"
  ],
  "landing_url": "https://doi.org/10.1172/jci207077",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research Article"
    ],
    [
      "openalex",
      "2403|T-cell and B-cell Immunology"
    ]
  ],
  "openalex": "W7204869410",
  "pdf_url": "http://www.jci.org/articles/view/207077/files/pdf",
  "pmcid": "PMC13722395",
  "pmid": "42678733",
  "published": "2026-09-01",
  "publisher": "American Society for Clinical Investigation",
  "ris": "https://research.draconitic.com/paper/fp14888k226hf.ris",
  "sources": [
    {
      "first_seen": "2026-11-03T12:22:54Z",
      "native_id": "PMC13722395",
      "source": "pmc",
      "url": "https://doi.org/10.1172/jci207077"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|T-cell and B-cell Immunology",
      "subfield": "immunology"
    }
  ],
  "title": "Enhancing Treg persistence by inhibiting necroptosis restrains autoimmune pathology",
  "title_text": "Enhancing Treg persistence by inhibiting necroptosis restrains autoimmune pathology",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:22:54Z",
  "url": "https://research.draconitic.com/paper/fp14888k226hf",
  "venue": "The Journal of Clinical Investigation",
  "versions": []
}