{
  "abstract": "Aberrant activation of the STING signaling pathway is involved with aging-related inflammation, yet no STING-targeting therapeutics are clinically approved. Here, we identify Omaveloxolone, an FDA-approved drug for Friedreich's ataxia, as a potent STING degrader (DC₅₀ = 118 nM, Dmax = 98.6%) via high-throughput screening. Omaveloxolone binds non-covalently to the base of the STING ligand-binding domain (LBD) with high affinity (KD = 21.4 nM) and exhibits crowbar-like behavior consistent with STING conformational destabilization: it hinders LBD closure, increases hydrophobic exposure, and reduces thermal stability. This conformational perturbation is proposed to enhance recognition by the E3 ubiquitin ligase HUWE1, leading to K27-linked ubiquitination at STING lysines K236/K347/K370 and proteasomal degradation. In vivo, Omaveloxolone depletes STING, suppresses downstream inflammatory signaling, and ameliorates aging-related inflammatory phenotypes in aged male mice. Because Omaveloxolone is also an established NRF2 activator, these in vivo benefits likely reflect dual modulation of inflammatory and antioxidant pathways. This study implicates Omaveloxolone as a molecular crowbar-like STING degrader and provides a mechanistic framework for targeting STING via conformational perturbation.",
  "abstract_shown": true,
  "affiliations": [
    "School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.",
    "Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.",
    "School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China.",
    "Department of Translational Medicine Platform, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.",
    "University of Chinese Academy of Sciences, Beijing, China.",
    "School of Pharmacy, Nanchang University, Nanchang, China.",
    "Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.",
    "Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. tengdan@simm.ac.cn.",
    "University of Chinese Academy of Sciences, Beijing, China. tengdan@simm.ac.cn.",
    "School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. myzheng@simm.ac.cn.",
    "Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. myzheng@simm.ac.cn.",
    "School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, China. myzheng@simm.ac.cn.",
    "University of Chinese Academy of Sciences, Beijing, China. myzheng@simm.ac.cn.",
    "School of Pharmacy, Nanchang University, Nanchang, China. myzheng@simm.ac.cn.",
    "School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China. slzhang@simm.ac.cn.",
    "Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China. slzhang@simm.ac.cn.",
    "University of Chinese Academy of Sciences, Beijing, China. slzhang@simm.ac.cn."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Jingyi Zhou"
    },
    {
      "affs": [
        2
      ],
      "name": "Xinyi Ma"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Bing Jiang"
    },
    {
      "affs": [
        1
      ],
      "name": "Zisheng Fan"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Penghua Li"
    },
    {
      "affs": [
        0,
        1,
        4
      ],
      "name": "Qi Dai"
    },
    {
      "affs": [
        0,
        1,
        4
      ],
      "name": "Yajie Wang"
    },
    {
      "affs": [
        1,
        5
      ],
      "name": "Min Wu"
    },
    {
      "affs": [
        6
      ],
      "name": "Qibang Sui"
    },
    {
      "affs": [
        0,
        1,
        4
      ],
      "name": "Ning Ma"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Ruirui Yang"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Haiwei Shen"
    },
    {
      "affs": [
        2
      ],
      "name": "Jingyi Meng"
    },
    {
      "affs": [
        1,
        5
      ],
      "name": "Manlin Huang"
    },
    {
      "affs": [
        0,
        1,
        4
      ],
      "name": "Zhiming Ge"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Jiusheng Lin",
      "orcid": "0000-0003-0574-9064"
    },
    {
      "affs": [
        7,
        8
      ],
      "name": "Dan Teng"
    },
    {
      "affs": [
        9,
        10,
        11,
        12,
        13
      ],
      "name": "Mingyue Zheng",
      "orcid": "0000-0002-3323-3092"
    },
    {
      "affs": [
        14,
        15,
        16
      ],
      "name": "Sulin Zhang",
      "orcid": "0000-0002-9167-4689"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5z8g9gc2qkqhf.bib",
  "cited_by": 0,
  "doi": "10.1038/s41467-026-77760-1",
  "fulltext_url": "https://europepmc.org/articles/PMC13719992",
  "id": "5z8g9gc2qkqhf",
  "issns": [
    "2041-1723"
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  "landing_url": "https://europepmc.org/article/MED/42957659",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
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      "2403|interferon and immune responses"
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  "pdf_url": "https://europepmc.org/articles/PMC13719992?pdf=render",
  "pmcid": "PMC13719992",
  "pmid": "42957659",
  "published": "2026-09-17",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/5z8g9gc2qkqhf.ris",
  "sources": [
    {
      "first_seen": "2026-11-01T00:20:45Z",
      "native_id": "MED:42957659",
      "source": "europepmc",
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      "native_id": "PMC13719992",
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      "url": "https://doi.org/10.1038/s41467-026-77760-1"
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  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|interferon and immune responses",
      "subfield": "immunology"
    }
  ],
  "title": "Omaveloxolone functions as a molecular crowbar-like degrader of STING to alleviate aging-related inflammation.",
  "title_text": "Omaveloxolone functions as a molecular crowbar-like degrader of STING to alleviate aging-related inflammation.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-03T12:20:57Z",
  "url": "https://research.draconitic.com/paper/5z8g9gc2qkqhf",
  "venue": "Nature communications",
  "versions": []
}