{
  "abstract": "Flap endonuclease 1 (FEN1), a key enzyme in DNA metabolism, exhibits oncogenic properties in various cancers. However, its functional role and underlying mechanisms in lung adenocarcinoma (LUAD) progression and tumor immunity remain poorly defined. Here, we demonstrate that FEN1 is significantly upregulated in LUAD tissues and serves as an independent prognostic factor for poor survival. Genetic depletion of FEN1 suppressed LUAD cell proliferation by inducing G0/G1 cell cycle arrest and cellular senescence, while significantly impairing migration and invasion capabilities. Mechanistically, integrated proteomic and molecular analyses revealed that FEN1 knockdown disrupts the carboxyl-terminal subunit of mucin 1 (MUC1-C)/PI3K/AKT autoregulatory loop, a critical driver of oncogenic signaling. Furthermore, FEN1 downregulation inhibited the MUC1-C/p65/ programmed death-ligand 1 (PD-L1) signaling axis, thereby alleviating tumor-mediated immunosuppression. This was evidenced by enhanced antitumor immunity, characterized by the local expansion of CD4⁺ T cells and restored effector function of CD8⁺ T cells, both in vitro and in vivo. Mechanistically, independent of its nuclease activity, FEN1 interacts with the N-terminus of eukaryotic translation initiation factor 4A3 (EIF4A3) to facilitate its binding to MUC1-C mRNA. Specifically, FEN1 is required for EIF4A3-mediated maintenance of both the transcript stability and translation efficiency of MUC1-C. Clinically, FEN1, MUC1-C, and PD-L1 are coordinately upregulated in LUAD tissues, and their co-expression predicts poor patient survival irrespective of EGFR mutation status. Our findings establish the FEN1/EIF4A3/MUC1-C axis as a novel mechanism driving LUAD progression by concurrently regulating intrinsic malignancy and extrinsic immune evasion, presenting FEN1 targeting as a promising dual-hit therapeutic strategy.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Oncology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, PR China. minwu@yzu.edu.cn.",
    "The First School of Clinical Medicine, Faculty of Medicine, Yangzhou University, Yangzhou, PR China. minwu@yzu.edu.cn.",
    "Department of Oncology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, PR China.",
    "The First School of Clinical Medicine, Faculty of Medicine, Yangzhou University, Yangzhou, PR China.",
    "Department of Clinical Laboratory, The Second Affiliated Hospital of Xuzhou Medical University, Xuzhou, PR China.",
    "Department of Pathology, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, PR China.",
    "Department of Clinical Laboratory, The Affiliated People's Hospital of Jiangsu University, Zhenjiang, PR China.",
    "Department of Oncology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, PR China. linyu@yzu.edu.cn.",
    "School of Basic Medical Sciences & School of Public Health, Faculty of Medicine, Yangzhou University, Yangzhou, PR China. linyu@yzu.edu.cn.",
    "Department of Oncology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, PR China. jjliu0105@yzu.edu.cn.",
    "School of Traditional Chinese Medicine, Faculty of Medicine, Yangzhou University, Yangzhou, PR China. jjliu0105@yzu.edu.cn."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Min Wu",
      "orcid": "0000-0002-9920-5721"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Benmeng Wu"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Xuebing Yan",
      "orcid": "0000-0001-9069-5907"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Zirui Wang"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Chunyan Mei"
    },
    {
      "affs": [
        4
      ],
      "name": "Xiaoshan Huang"
    },
    {
      "affs": [
        5
      ],
      "name": "Guorui Li"
    },
    {
      "affs": [
        6
      ],
      "name": "Ji Pang"
    },
    {
      "affs": [
        7,
        8
      ],
      "name": "Lin Yu"
    },
    {
      "affs": [
        9,
        10
      ],
      "name": "Jingjing Liu",
      "orcid": "0000-0002-8153-6653"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/eya83wfceb9fp.bib",
  "cited_by": 0,
  "doi": "10.1038/s41419-026-09260-5",
  "fulltext_url": "https://europepmc.org/articles/PMC13675245",
  "id": "eya83wfceb9fp",
  "issns": [
    "2041-4889"
  ],
  "landing_url": "https://europepmc.org/article/MED/42888188",
  "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": [
    [
      "openalex",
      "2730|Cancer Immunotherapy and Biomarkers"
    ]
  ],
  "openalex": "W7208820370",
  "pdf_url": "https://europepmc.org/articles/PMC13675245?pdf=render",
  "pmcid": "PMC13675245",
  "pmid": "42888188",
  "published": "2026-09-05",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/eya83wfceb9fp.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:18Z",
      "native_id": "MED:42888188",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42888188"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Immunotherapy and Biomarkers",
      "subfield": "oncology"
    }
  ],
  "title": "Targeting FEN1 disrupts EIF4A3-mediated MUC1-C autoregulation: a novel strategy to suppress lung adenocarcinoma progression.",
  "title_text": "Targeting FEN1 disrupts EIF4A3-mediated MUC1-C autoregulation: a novel strategy to suppress lung adenocarcinoma progression.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:18Z",
  "url": "https://research.draconitic.com/paper/eya83wfceb9fp",
  "venue": "Cell death & disease",
  "versions": []
}