{
  "abstract": "NRF2 oncogenic activation (NRFA)-subtype esophageal squamous cell carcinoma (ESCC) patients exhibit poor prognosis and limited response to conventional therapies due to excessive NRF2 protein accumulation. Here, we identify L013, an NRF2 degrader, through high-content screening of 725 cereblon (CRBN) ligand-based degraders. Our results indicate that L013 effectively reduces NRF2 abundance and decreases NFE2L2 mRNA expression in ESCC cells. Mechanistically, L013 promotes NRF2 ubiquitination through a ubiquitin-proteasome system (UPS)-associated process involving Cullin-dependent E3 ligase activity, while its A51-derived scaffold independently contributes to NRF2 suppression, at least in part, by impairing NFE2L2 transcriptional output. In preclinical models, L013 reduces NRF2 levels and suppresses tumor growth in patient-derived organoids (PDOs) of ESCC and lung squamous cell carcinoma (LUSC), as well as ESCC xenograft models. No overt systemic toxicity occurs under the tested dosing regimen. Our findings establish L013 as a promising therapeutic candidate for NRFA-subtype ESCC patients, offering a potential strategy to target NRF2-driven oncogenesis.",
  "abstract_shown": true,
  "affiliations": [
    "State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China",
    "MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Tsinghua University, Beijing 100084, China",
    "Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China",
    "Institute of Cancer Research, Henan Academy of Innovations in Medical Sciences, Zhengzhou, Henan Province 450000, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xiao Yu"
    },
    {
      "affs": [
        1
      ],
      "name": "Yue Wu"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiuyun Sun"
    },
    {
      "affs": [
        2
      ],
      "name": "Rui Han"
    },
    {
      "affs": [
        1
      ],
      "name": "Yi Cai"
    },
    {
      "affs": [
        1
      ],
      "name": "Wei Zeng"
    },
    {
      "affs": [
        0
      ],
      "name": "Yang Li"
    },
    {
      "affs": [
        0
      ],
      "name": "Yuhao Wang"
    },
    {
      "affs": [
        0
      ],
      "name": "Yahui Zhao"
    },
    {
      "affs": [
        1
      ],
      "name": "Yu Rao"
    },
    {
      "affs": [
        0,
        3
      ],
      "name": "Zhihua Liu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/59d617jj07a43.bib",
  "cited_by": 0,
  "doi": "10.1016/j.xcrm.2026.103046",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13710151/",
  "id": "59d617jj07a43",
  "issns": [
    "2666-3791"
  ],
  "landing_url": "https://doi.org/10.1016/j.xcrm.2026.103046",
  "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",
      "Article"
    ],
    [
      "openalex",
      "1312|Genomics, phytochemicals, and oxidative stress"
    ]
  ],
  "openalex": "W7212273819",
  "pdf_url": null,
  "pmcid": "PMC13710151",
  "pmid": "42727581",
  "published": "2026-09-11",
  "publisher": "Elsevier",
  "ris": "https://research.draconitic.com/paper/59d617jj07a43.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T12:21:10Z",
      "native_id": "PMC13710151",
      "source": "pmc",
      "url": "https://doi.org/10.1016/j.xcrm.2026.103046"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Genomics, phytochemicals, and oxidative stress",
      "subfield": "molecular-biology"
    }
  ],
  "title": "L013 promotes NRF2 degradation in NRFA-subtype esophageal squamous cell carcinoma",
  "title_text": "L013 promotes NRF2 degradation in NRFA-subtype esophageal squamous cell carcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:21:10Z",
  "url": "https://research.draconitic.com/paper/59d617jj07a43",
  "venue": "Cell Reports Medicine",
  "versions": []
}