{
  "abstract": "Neuroblastoma is characterized by marked molecular heterogeneity, and additional biological states contributing to aggressive disease remain incompletely defined. Ferritinophagy-related genes connect ferritin turnover, intracellular iron regulation, and autophagy-associated processes, but whether they delineate clinically relevant iron-autophagy transcriptional states in neuroblastoma is unclear. We aimed to identify clinically relevant iron-autophagy transcriptional states in neuroblastoma and assess their cross-cohort transferability, cellular distribution, and treatment-associated differences. We integrated bulk transcriptomic, single-cell RNA-sequencing, and region-of-interest (ROI)-level GeoMx Digital Spatial Profiling datasets. Ferritinophagy-related genes were used as an entry point for unsupervised classification in the GSE62564 discovery cohort, followed by construction of a locked 34-gene centroid classifier and a continuous C1-associated axis, which were projected without gene reselection or refitting into three independent bulk cohorts. A four-gene iron-autophagy imbalance index (IA4) was derived from opposing iron-handling and autophagy-associated transcriptional components. Single-cell and spatial analyses assessed malignant-cell expression, treatment-associated differences within malignant cells, and clinical-risk associations. Two transcriptional states were identified. In GSE62564, C1 comprised 180 of 498 tumors and was associated with inferior overall survival (OS) [univariable hazard ratio (HR), 16.51; 95% confidence interval (CI): 9.52-28.63] and event-free survival (EFS) (HR, 4.24; 95% CI: 3.13-5.74); at 5 years, C1 was associated with a 1.45-year loss of restricted mean OS (95% CI: 1.18-1.72). The associations remained significant after adjustment for age, stage, and MYCN status (OS HR, 5.03; 95% CI: 2.53-9.99; EFS HR, 2.00; 95% CI: 1.30-3.08). In three independent bulk cohorts, a 1-standard deviation (SD) increase in the continuous C1 score was associated with inferior OS (HR range, 1.58-2.44; all P<0.001). C1 tumors showed coordinated malignant and iron-autophagy-associated programs. IA4, defined from TFRC, PCBP1, PINK1, and ATG16L1, correlated with the continuous C1 axis in 34 pretreatment tumor ROIs (Spearman rho =0.64, P=4.3×10-5) and remained robust in leave-one-gene-out analyses. In 22 paired longitudinal donors, the malignant-cell weighted C1 score decreased after treatment (P=0.002), and the cycle-residual component remained lower after adjustment for S-phase and G2/M activity (P=0.01). Using ferritinophagy-related genes as a discovery framework, this study identifies a clinically adverse iron-autophagy imbalance state in neuroblastoma and provides a compact transcriptional representation through IA4. The findings establish a framework for future functional investigation without implying direct measurement of ferritinophagic flux, intracellular iron, or ferroptosis sensitivity.",
  "abstract_shown": true,
  "affiliations": [
    "National Clinical Research Center for Cancer-Translational Research Center for Cell Immunotherapy, Department of Cancer Immunology and Immunotherapy, National Clinical Research Center for Cancer, Tianjin Cancer Hospital Airport Hospital, Tianjin, China.",
    "Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin, China.",
    "Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China.",
    "Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.",
    "Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Li Zhang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Xiaomeng Wang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Zhanbo Wu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yinan Dong"
    },
    {
      "affs": [
        0,
        1,
        2,
        3,
        4
      ],
      "name": "Runmei Li"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/a0bg5cc44pmnh.bib",
  "cited_by": 0,
  "doi": "10.21037/tp-2026-0827",
  "fulltext_url": "https://europepmc.org/articles/PMC13739828",
  "id": "a0bg5cc44pmnh",
  "issns": [
    "2224-4336",
    "2224-4344"
  ],
  "landing_url": "https://europepmc.org/article/MED/42996735",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2730|Neuroblastoma Research and Treatments"
    ]
  ],
  "openalex": "W7223694860",
  "pdf_url": "https://europepmc.org/articles/PMC13739828?pdf=render",
  "pmcid": "PMC13739828",
  "pmid": "42996735",
  "published": "2026-09-30",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/a0bg5cc44pmnh.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T15:20:41Z",
      "native_id": "MED:42996735",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42996735"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Neuroblastoma Research and Treatments",
      "subfield": "oncology"
    }
  ],
  "title": "Integrated transcriptomic profiling identifies a clinically adverse iron-autophagy imbalance state in neuroblastoma.",
  "title_text": "Integrated transcriptomic profiling identifies a clinically adverse iron-autophagy imbalance state in neuroblastoma.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T15:20:41Z",
  "url": "https://research.draconitic.com/paper/a0bg5cc44pmnh",
  "venue": "Translational pediatrics",
  "versions": []
}