{
  "abstract": "Background\n\nHigh-risk human papillomavirus (HPV)-associated cervical carcinogenesis involves oxidative stress, mitochondrial dysfunction, and altered non-apoptotic cell-death programs. Ferroptosis and mitochondrial permeability transition (MPT)-driven necrosis may share upstream stress-related transcriptional signals, but their joint pathway-state features in cervical cancer remain incompletely characterized.Methods\n\nWe constructed a directionality-aware net pathway activity framework using evidence-audited ferroptosis-promoting, ferroptosis-inhibitory, MPT-promoting, and MPT-inhibitory gene sets in 304 TCGA-CESC primary tumors. The score was benchmarked against ssGSEA, GSVA, and PLAGE and evaluated in controlled simulations. For feature prioritization, score-defining genes were excluded from predictors and Elastic Net feature selection, XGBoost tuning, and model fitting were performed strictly within repeated nested cross-validation. Outer-test SHAP, model-sensitivity analysis, and a 200-permutation complete-pipeline test were used for interpretation and robustness assessment. External validation used GSE138080, GSE63514, GSE223804, and GSE151666.Results\n\nCombinedNet showed moderate-to-high concordance with ssGSEA, GSVA, and PLAGE (Spearman rho = 0.735, 0.882, and 0.943, respectively), while 1,300 controlled simulations showed strong recovery of the latent promoter-minus-inhibitor balance across scenarios and effect sizes (mean rho = 0.944; mean sign-recovery accuracy = 0.902; mean standardized RMSE = 0.305). The leakage-resistant repeated nested-CV model yielded AUC = 0.780 (95% CI 0.766-0.795); a matched complete-pipeline permutation test gave empirical p = 0.005. Stability-weighted SHAP and perturbation prioritized CKMT1B and KLK13, whereas GNA13, PANX2, and all five sterol genes were not selected in any of 25 outer-fold models. The sterol genes retained modest score correlations but showed no model sensitivity. Across three lesion-progression cohorts, no pathway score remained associated with stage after FDR correction; in the cancer-only GSE151666 RNA-seq cohort, CombinedNet also showed no FIGO-stage trend.Conclusion\n\nThis study supports directionality-aware transcriptomic scoring and a leakage-resistant feature-prioritization framework, but does not support GNA13/PANX2 or cholesterol-biosynthesis signals as stable model drivers or the composite score as a validated lesion-stage biomarker. The findings remain hypothesis-generating and require experimental validation.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Pain Medicine, Shaoxing People's Hospital, Shaoxing, China.",
    "Hangzhou Sun Taihe Traditional Chinese Medicine and Pharmacy, Hangzhou, China.",
    "Hangzhou Fuyang Hospital of TCM Orthopedics and Traumatology, Hangzhou, China.",
    "Reproductive Center, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Huiying Zhang"
    },
    {
      "affs": [
        1
      ],
      "name": "Yidong Zhu"
    },
    {
      "affs": [
        2
      ],
      "name": "Weijie Shao"
    },
    {
      "affs": [
        3
      ],
      "name": "Kai Xu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/23eh21d8qthqk.bib",
  "cited_by": 0,
  "doi": "10.3389/fgene.2026.1930345",
  "fulltext_url": "https://europepmc.org/articles/PMC13677934",
  "id": "23eh21d8qthqk",
  "issns": [
    "1664-8021"
  ],
  "landing_url": "https://europepmc.org/article/MED/42898594",
  "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": "W7220472433",
  "pdf_url": "https://europepmc.org/articles/PMC13677934?pdf=render",
  "pmcid": "PMC13677934",
  "pmid": "42898594",
  "published": "2026-10-05",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/23eh21d8qthqk.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:37Z",
      "native_id": "MED:42898594",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42898594"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Ferroptosis and cancer prognosis",
      "subfield": "general"
    }
  ],
  "title": "Interpretable machine learning prioritizes transcriptomic features associated with ferroptosis-mitochondrial permeability transition net activity states in cervical cancer.",
  "title_text": "Interpretable machine learning prioritizes transcriptomic features associated with ferroptosis-mitochondrial permeability transition net activity states in cervical cancer.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:37Z",
  "url": "https://research.draconitic.com/paper/23eh21d8qthqk",
  "venue": "Frontiers in genetics",
  "versions": []
}