{
  "abstract": "Background: Acquired resistance limits the benefit of osimertinib in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD), and epigenetic silencing may contribute to this process. This study aimed to determine whether promoter hypermethylation-associated silencing of zinc finger protein 471 (ZNF471) contributes to resistance and whether β-hydroxybutyrate (BHB) can restore ZNF471 expression. Methods: ZNF471 expression and promoter methylation were analyzed in public datasets, clinical samples, and osimertinib-sensitive and resistant cell lines. Functional assays and signaling analyses were performed in vitro, and BHB treatment and ZNF471 overexpression were evaluated in xenografts. Results: ZNF471 was downregulated and hypermethylated in LUAD, and low expression was associated with advanced stage and poor survival. ZNF471 restoration reduced the osimertinib half-maximal inhibitory concentration, inhibited migration, invasion, and tumorsphere formation, and was associated with suppression of PI3K/AKT/mTOR signaling, whereas ZNF471 knockdown had the opposite effect. BHB increased ZNF471 expression, reduced methylation-specific PCR signals, and synergized with osimertinib in resistant cells in vitro. In xenografts, BHB treatment and ZNF471 overexpression each inhibited tumor growth. Conclusions: ZNF471 is an epigenetically silenced modulator of osimertinib sensitivity in LUAD. BHB may enhance osimertinib response by reactivating ZNF471. ZNF471 is an epigenetically silenced modulator of osimertinib sensitivity in LUAD. BHB may enhance osimertinib response by reactivating ZNF471. Taken together, these findings suggest that BHB is associated with ZNF471 re-expression and reduced osimertinib resistance-associated phenotypes in LUAD cells, although whether ZNF471 is required for this effect remains to be determined.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pathology, Yueyang People’s Hospital of Hunan Normal University, Yueyang, China",
    "School of Basic Medical Sciences, Hunan Normal University Health Science Center, Hunan Normal University, Changsha, China",
    "Department of Orthopedics, Yueyang People’s Hospital of Hunan Normal University, Yueyang, China",
    "Department of Science and Education, Yueyang People’s Hospital of Hunan Normal University, Yueyang, China"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Dade Feng"
    },
    {
      "affs": [
        0
      ],
      "name": "Huiting Yan"
    },
    {
      "affs": [
        1
      ],
      "name": "Qian Ni"
    },
    {
      "affs": [
        1
      ],
      "name": "Zirui Peng"
    },
    {
      "affs": [
        2
      ],
      "name": "Xiong Xu"
    },
    {
      "affs": [
        3
      ],
      "name": "Yanfang Liang"
    },
    {
      "affs": [
        0
      ],
      "name": "Chongmei Liu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/crz8af9j72ny3.bib",
  "cited_by": 0,
  "doi": "10.32604/or.2026.087712",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13732338/",
  "id": "crz8af9j72ny3",
  "issns": [
    "0965-0407",
    "1555-3906"
  ],
  "landing_url": "https://doi.org/10.32604/or.2026.087712",
  "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",
      "2740|Lung Cancer Treatments and Mutations"
    ]
  ],
  "openalex": "W7223180985",
  "pdf_url": "https://www.techscience.com/or/online/detail/28747/TSP_OR_87712.pdf",
  "pmcid": "PMC13732338",
  "pmid": "42985469",
  "published": "2026-10-28",
  "publisher": "Tech Science Press",
  "ris": "https://research.draconitic.com/paper/crz8af9j72ny3.ris",
  "sources": [
    {
      "first_seen": "2026-11-08T12:22:20Z",
      "native_id": "PMC13732338",
      "source": "pmc",
      "url": "https://doi.org/10.32604/or.2026.087712"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Lung Cancer Treatments and Mutations",
      "subfield": "general"
    }
  ],
  "title": "Epigenetic Silencing of ZNF471 Contributes to Osimertinib Resistance in Lung Adenocarcinoma: β-Hydroxybutyrate Associates with ZNF471 Re-Expression and Reduced Resistance-Associated Phenotypes",
  "title_text": "Epigenetic Silencing of ZNF471 Contributes to Osimertinib Resistance in Lung Adenocarcinoma: β-Hydroxybutyrate Associates with ZNF471 Re-Expression and Reduced Resistance-Associated Phenotypes",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T12:22:20Z",
  "url": "https://research.draconitic.com/paper/crz8af9j72ny3",
  "venue": "Oncology Research",
  "versions": []
}