{
  "abstract": "Excessive alcohol consumption poses significant health risks and is closely associated with oxidative damage. The KEAP1-NRF2-ARE signaling pathway serves as the primary antioxidant system. However, current small molecule inhibitors are all covalently bound to KEAP1, meaning that once bound, they are not easily dissociated, while continuous inhibition of KEAP1 exhibits severe side effects. In this study, BLI, CETSA, Pull-down, Co-IP and HDX-MS assay analysis were conducted to detect the KEAP1 binding behavior of natural product, capsaicin (CAP), both in vitro and in cells. The ethanol-induced acute gastric mucosal damage rat model was also established to evaluate the therapeutic effect of CAP. Our findings demonstrated that CAP mitigated mitochondrial damage, facilitated the nuclear translocation of NRF2, leading to the up-regulation of downstream antioxidant response elements, HMOX1, TXN, GSS and NQO1 in GES-1 cells. Furthermore, CAP directly bind to KEAP1 and inhibit the interaction between KEAP1 and NRF2. In the KEAP1-knockout 293T cells, CAP failed to activate NRF2 expression. We identified that CAP non-covalently bound to Kelch domain and allosterically regulated three specific regions of KEAP1 : L342-L355, D394-G423 and N482-N495. To improve drug solubility and delivery efficiency, we developed IR-Dye800 modified albumin coated CAP nanoparticles. The nanoparticles significantly reduced the gastric mucosal inflammation and activated NRF2 downstream genes in vivo . Our hypothesis was further verified our hypothesis in Nfe2l2-knockout mice. This study provides new insights that CAP is a safe and novel NRF2 agonist by allosterically regulating KEAP1, which may contribute to the development of lead drugs for oxidative stress-related illness, e.g. aging, cancer, neurodegenerative and cardiovascular diseases.",
  "abstract_shown": true,
  "affiliations": [
    "School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, People’s Republic of China",
    "School of Life Sciences, Tianjin University, 92 Weijin Road, Nankai District, Tianjin 300072, People's Republic of China",
    "Tianjin JiAnKang Bio&TCM-technology Development Co., Ltd. Tianjin, 300457, People’s Republic of China",
    "Tianjin JiAnKang Bio&TCM-technology Development Co., Ltd. Tianjin, 300457, People's Republic of China",
    "CAS & THHDG (TIANJIN) RURAL REVITALIZATION INDUSTRY DEVELOPMENT CO., LTD. Room 280, Fujian Building, Chunhua Street, Hedong District, Tianjin, 00000, China",
    "Peiyang Park Campus, Tianjin University, No.135 Yaguan Road, Haihe Education Park, Tianjin, 30035, China",
    "CAS & THHDG (TIANJIN) RURAL REVITALIZATION INDUSTRY DEVELOPMENT CO., LTD. Room 2803, Fujian Building, Chunhua Street, Hedong District, Tianjin, 300000, China",
    "Department of Molecular Pharmacology, Tianjin Medical University Cancer Institute & Hospital",
    "Key Laboratory of Cancer Prevention and Therapy, Tianjin",
    "National Clinical Research Center for Cancer",
    "Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China",
    "Peiyang Park Campus, Tianjin University, No.135 Yaguan Road, Haihe Education Park, Tianjin, 300354, China",
    "Department of Molecular Pharmacology, Tianjin Medical University Cancer Institute & Hospital; National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin; Tianjin’s Clinical Research Center for Cancer, Tianjin 300060, China",
    "Institute for TCM-X, MOE Key Laboratory of Bioinformatics, Bioinformatics Division, BNRist, Department of Automation, Tsinghua University, No. 30 Shuangqing Road, Haidian District, Beijing 100084, People's Republic of China",
    "Institute for TCM-X, MOE Key Laboratory of Bioinformatics, Bioinformatics Division, BNRist, Department of Automation, Tsinghua University, No. 30 Shuangqing Road, Haidian District, Beijing 100084, People’s Republic of China"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 21,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Xiaoning Gao",
      "orcid": "0009-0005-0668-7928"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Wuyan Guo"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Peiyuan Liu",
      "orcid": "0009-0002-8411-236X"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Mingyue Yuwen"
    },
    {
      "affs": [
        1
      ],
      "name": "Hongyu Ren"
    },
    {
      "affs": [
        1
      ],
      "name": "Shengtao Hu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Zixiang Liu",
      "orcid": "0000-0002-6178-4406"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ruyang Tan",
      "orcid": "0009-0003-9874-607X"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Kairui Liu",
      "orcid": "0009-0000-0166-646X"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Zhiru Yang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Junli Ba"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xue Tao Bai",
      "orcid": "0000-0002-8636-3843"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Shiti Shama"
    },
    {
      "affs": [
        0,
        5
      ],
      "name": "Cong Tang",
      "orcid": "0000-0003-1661-6793"
    },
    {
      "affs": [
        6,
        7,
        8,
        9,
        10
      ],
      "name": "Kai Miao"
    },
    {
      "affs": [
        11,
        1
      ],
      "name": "Haozhi Pei"
    },
    {
      "affs": [
        12,
        1
      ],
      "name": "Liren Liu",
      "orcid": "0000-0001-7786-7874"
    },
    {
      "affs": [
        0,
        7,
        13,
        8,
        9,
        10
      ],
      "name": "Cheng Zhu",
      "orcid": "0000-0003-0260-6287"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Tao Wang",
      "orcid": "0000-0003-1490-7407"
    },
    {
      "affs": [
        12,
        14
      ],
      "name": "Bo Zhang",
      "orcid": "0000-0003-2649-4240"
    },
    {
      "affs": [
        0
      ],
      "name": "Jun Gu Kang",
      "orcid": "0000-0002-6934-4341"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0h7sd1nkcq93r.bib",
  "cited_by": 8,
  "doi": "10.7554/elife.97632.4",
  "fulltext_url": null,
  "id": "0h7sd1nkcq93r",
  "issns": [
    "2050-084X"
  ],
  "landing_url": "https://doi.org/10.7554/elife.97632.4",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Genomics, phytochemicals, and oxidative stress"
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  "pdf_url": "https://elifesciences.org/download/aHR0cHM6Ly9jZG4uZWxpZmVzY2llbmNlcy5vcmcvYXJ0aWNsZXMvOTc2MzIvZWxpZmUtOTc2MzItdjEucGRmP2Nhbm9uaWNhbFVyaT1odHRwczovL2VsaWZlc2NpZW5jZXMub3JnL2FydGljbGVzLzk3NjMy/elife-97632-v1.pdf?_hash=3Q6p%2B5qJQMFfJHpD%2FByr%2FHdPkQ2AohpyLJiiDkPZrfE%3D",
  "pmcid": null,
  "pmid": null,
  "published": "2026-06-09",
  "publisher": "eLife Sciences Publications Ltd",
  "ris": "https://research.draconitic.com/paper/0h7sd1nkcq93r.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:48Z",
      "native_id": "W4390660701",
      "source": "openalex",
      "url": "https://doi.org/10.7554/elife.97632.4"
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  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Genomics, phytochemicals, and oxidative stress",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction",
  "title_text": "Capsaicin acts as a novel NRF2 agonist to suppress ethanol induced gastric mucosa oxidative damage by directly disrupting the KEAP1-NRF2 interaction",
  "type": "peer-reviewed",
  "updated_at": "2026-11-04T13:21:07Z",
  "url": "https://research.draconitic.com/paper/0h7sd1nkcq93r",
  "venue": "eLife",
  "versions": []
}