{
  "abstract": "Background: Brain metastasis remains a major cause of mortality in patients with advanced non-small cell lung cancer, whereas effective radiosensitization strategies are constrained by heterogeneous tumor responses and the tolerance of normal brain tissue. Ferumoxytol, a clinically used iron oxide nanoparticle formulation, has emerging translational potential as an iron-modulating agent. However, whether Ferumoxytol enhances radiosensitivity in brain-metastatic lung cancer cells and the mechanisms underlying this effect remain unclear.\n\nMethods: PC-9 lung adenocarcinoma cells and NCI-H1915 brain-metastatic lung adenocarcinoma cells were used to evaluate ferumoxytol under basal and irradiated conditions. Ferroptosis-associated phenotypes, oxidative stress, clonogenic survival, and cell-cycle distribution were assessed. TMT-based proteomics and public single-cell and spatial transcriptomic analyses were used for candidate prioritization and disease-context support. NCOA4 was evaluated by siRNA-mediated loss of function, single-dose clonogenic assays, time-resolved NCOA4/FTH1 immunoblotting, bafilomycin A1-based autophagic-flux analysis, and endogenous NCOA4-FTH1 co-immunoprecipitation.\n\nResults: Ferumoxytol induced mitochondrial, biochemical, and molecular changes consistent with ferroptosis and enhanced irradiation-associated ROS accumulation, lipid peroxidation, and loss of clonogenic survival. Proteomic analysis prioritized NCOA4, while public transcriptomic analyses provided associative disease-context support. In H1915 cells, NCOA4 silencing attenuated combined-treatment Fe ²⁺ accumulation, oxidative stress, and γ-H2AX induction. The incremental reduction in colony formation produced by adding ferumoxytol to irradiation was also reduced after NCOA4 knockdown in H1915 cells and was no longer significant in PC-9 cells. Time-resolved immunoblotting showed marked FTH1 accumulation rather than net FTH1 depletion, with a late reduction in NCOA4. Bafilomycin A1 caused further LC3B-II and SQSTM1/p62 accumulation under IR + F, consistent with ongoing autophagic turnover, whereas co-immunoprecipitation showed greater normalized recovery of FTH1 in NCOA4 immunoprecipitates after IR + F.\n\nConclusion: Ferumoxytol enhances ferroptosis-associated oxidative injury and radiosensitivity in the tested lung cancer cell models. The combined loss-of-function, autophagic-flux, and protein-interaction data support the involvement of NCOA4-associated ferritin handling and iron mobilization. However, the observed FTH1 accumulation and the absence of iron-chelator rescue, cargo-specific lysosomal tracking, and in vivo validation preclude a definitive claim of canonical ferritinophagy or clinical efficacy.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Radiation Oncology, The Affiliated Lianyungang Hospital of Xuzhou Medical University/The First People’s Hospital of Lianyungang",
    "Department of Radiation Oncology, The First People’s Hospital of Lianyungang/Lianyungang Clinical College of Nanjing Medical University",
    "Lianyungang Medical-Education Innovation and Research Center, Nanjing Medical University",
    "Department of Radiation Oncology, Southeast University Affiliated Xuzhou Central Hospital"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Ziqiang Shen"
    },
    {
      "affs": [
        0
      ],
      "name": "Jiangrui Zhu"
    },
    {
      "affs": [
        0
      ],
      "name": "Yongliu Yang"
    },
    {
      "affs": [
        0
      ],
      "name": "Jing Yang"
    },
    {
      "affs": [
        0
      ],
      "name": "Lisha Rao"
    },
    {
      "affs": [
        3
      ],
      "name": "Chong Zhou"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Youyou Xia"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3462qp8t12fqw.bib",
  "cited_by": 0,
  "doi": "10.3389/fphar.2026.1883092",
  "fulltext_url": "https://europepmc.org/articles/PMC13713803",
  "id": "3462qp8t12fqw",
  "issns": [
    "1663-9812"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1883092/full",
  "language": "eng",
  "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",
      "Original Research"
    ],
    [
      "openalex",
      "2740|Ferroptosis and cancer prognosis"
    ]
  ],
  "openalex": "W7221835324",
  "pdf_url": "https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1883092/pdf",
  "pmcid": "PMC13713803",
  "pmid": "42953094",
  "published": "2026-10-14",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/3462qp8t12fqw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:06Z",
      "native_id": "10.3389/fphar.2026.1883092",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1883092/full"
    },
    {
      "first_seen": "2026-10-31T00:20:41Z",
      "native_id": "MED:42953094",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42953094"
    },
    {
      "first_seen": "2026-11-01T12:21:25Z",
      "native_id": "PMC13713803",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fphar.2026.1883092"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "issn:1663-9812",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Ferumoxytol potentiates ferroptotic radiosensitization through NCOA4-associated iron mobilization in brain-metastatic lung cancer cells",
  "title_text": "Ferumoxytol potentiates ferroptotic radiosensitization through NCOA4-associated iron mobilization in brain-metastatic lung cancer cells",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:21:25Z",
  "url": "https://research.draconitic.com/paper/3462qp8t12fqw",
  "venue": "Frontiers in Pharmacology",
  "versions": []
}