{
  "abstract": "Background/Objectives: Zinc homeostasis has emerged as an important regulator of cancer biology, yet the biological and clinical significance of zinc transporter-associated transcriptional programs in head and neck squamous cell carcinoma (HNSCC) remains poorly understood. This study aimed to identify zinc transporter-associated epithelial tumor cell states and evaluate their molecular and clinical significance. Methods: Single-cell RNA sequencing data from an HNSCC cohort were analyzed to identify epithelial tumor cell populations associated with zinc transporter expression and to characterize their molecular features. A ZIP-active transcriptional signature was subsequently applied to The Cancer Genome Atlas (TCGA)-HNSCC cohort to evaluate biological characteristics, immune features, survival outcomes, and the influence of NFE2L2/KEAP1/CUL3 mutation status. Results: A distinct epithelial tumor cell population characterized by coordinated upregulation of SLC39A3 and SLC39A4 was identified and designated the ZIP-active tumor cell state. This population showed NRF2-associated oxidative stress adaptation, glutathione metabolism, and ferroptosis suppression, together with increased NRF2 activity. In the TCGA-HNSCC cohort, a high ZIP-active score was associated with oxidative stress adaptation, reduced T-cell-related immune signatures, and poorer overall survival. NFE2L2/KEAP1/CUL3-mutant tumors showed higher ZIP-active and NRF2-related scores than wild-type tumors, while NRF2-related metabolic features remained associated with ZIP activity in both groups. Conclusions: The ZIP-active tumor cell state represents an NRF2-linked metabolic program associated with oxidative stress adaptation, immune alterations, and adverse prognosis in HNSCC. Its persistence across NFE2L2/KEAP1/CUL3 mutation groups suggests that ZIP activity reflects NRF2-related tumor biology beyond genomic alterations alone.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi 371-8511, Gunma, Japan."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Hideyuki Takahashi",
      "orcid": "0000-0002-2465-3992"
    },
    {
      "affs": [
        0
      ],
      "name": "Miho Uchida"
    },
    {
      "affs": [
        0
      ],
      "name": "Kaoru Takahashi"
    },
    {
      "affs": [
        0
      ],
      "name": "Hiroyuki Hagiwara"
    },
    {
      "affs": [
        0
      ],
      "name": "Hiroe Tada"
    },
    {
      "affs": [
        0
      ],
      "name": "Toshiyuki Matsuyama"
    },
    {
      "affs": [
        0
      ],
      "name": "Kazuaki Chikamatsu",
      "orcid": "0000-0002-7739-0102"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0v03167n8exmw.bib",
  "cited_by": 0,
  "doi": "10.3390/cancers18193104",
  "fulltext_url": "https://europepmc.org/articles/PMC13663997",
  "id": "0v03167n8exmw",
  "issns": [
    "2072-6694"
  ],
  "landing_url": "https://europepmc.org/article/MED/42882799",
  "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",
      "2740|Ferroptosis and cancer prognosis"
    ]
  ],
  "openalex": "W7214203736",
  "pdf_url": "https://europepmc.org/articles/PMC13663997?pdf=render",
  "pmcid": "PMC13663997",
  "pmid": "42882799",
  "published": "2026-09-24",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/0v03167n8exmw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:16Z",
      "native_id": "MED:42882799",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42882799"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "issn:2072-6694",
      "subfield": "oncology"
    }
  ],
  "title": "A ZIP-Active Tumor Cell State Defines an NRF2-Associated Ferroptosis-Resistant and Immune-Cold Transcriptional Program in Head and Neck Squamous Cell Carcinoma.",
  "title_text": "A ZIP-Active Tumor Cell State Defines an NRF2-Associated Ferroptosis-Resistant and Immune-Cold Transcriptional Program in Head and Neck Squamous Cell Carcinoma.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:16Z",
  "url": "https://research.draconitic.com/paper/0v03167n8exmw",
  "venue": "Cancers",
  "versions": []
}