{
  "abstract": "Background: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to gemcitabine and arises in a profoundly hypoxic tumor microenvironment. However, the molecular link between hypoxic adaptation and ferroptosis evasion remains incompletely understood. We investigated sulfide:quinone oxidoreductase (SQOR), a mitochondrial enzyme that couples hydrogen sulfide oxidation to coenzyme Q (CoQ) reduction, as a hypoxia-responsive regulator of ferroptosis sensitivity.\n\nMethods: A tissue microarray from 102 patients with PDAC was analyzed for hypoxia markers, SQOR, 4-hydroxynonenal (4-HNE), glutathione peroxidase 4 (GPX4), and ferroptosis suppressor protein 1 (FSP1), together with treatment response and survival. Mechanistic studies combined hypoxia time-course experiments with SQOR knockdown, wild-type overexpression, and a catalytically inactive mutant; electron-donor testing; CoQ redox and lipidomic profiling; GPX4/FSP1/dihydroorotate dehydrogenase (DHODH) epistasis; and death-mode rescue assays. Therapeutic relevance was evaluated in gemcitabine-resistant cell lines, eight patient-derived organoid lines, and xenograft models.\n\nResults: SQOR protein H-scores showed moderate positive associations with CAIX and HIF-1α (Spearman ρ = 0.473 and 0.438; BH-adjusted q = 3.92544 × 10−6 and 1.57881 × 10−5, respectively) and an inverse association with the lipid-peroxidation marker 4-hydroxynonenal (ρ = −0.465; q = 4.13981 × 10−6) and higher SQOR abundance was associated with shorter overall survival after multivariable adjustment for GPX4 and FSP1 (adjusted hazard ratio, 1.87). Hypoxia increased SQOR expression and the CoQH2/total CoQ ratio while suppressing lipid peroxidation; these effects required SQOR catalytic activity, and donor-perturbation experiments implicated H2S more strongly than selenium metabolism under the tested conditions. SQOR loss increased relative signals annotated as oxidized arachidonoyl- and adrenoyl-phosphatidylethanolamines and enhanced ferroptosis sensitivity. SQOR loss synergized with inhibition of GPX4, FSP1, and DHODH, supporting a nonredundant contribution to ferroptosis control; pharmacological rescue was more pronounced with ferroptosis-directed agents than with a caspase inhibitor. Combining the putative SQOR inhibitor with ferroptosis induction lowered gemcitabine IC50 values in resistant models, without restoring parental sensitivity.\n\nConclusion: The tested PDAC models support SQOR as a hypoxia-responsive, catalysis-dependent contributor to mitochondrial ferroptosis defense and gemcitabine resistance. The tissue correlations are associative and do not establish that hypoxia suppresses lipid peroxidation through SQOR in patients. These findings support further preclinical evaluation of SQOR-directed strategies to improve gemcitabine sensitivity in PDAC.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Emergency Surgery, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China , , ,",
    "Department of Hepatobiliary and Pancreatic Surgery, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China , , ,",
    "General Practice Center, Sichuan Provincial People’s Hospital, School of Medicine, University of Electronic Science and Technology of China , , ,"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Guixiang Huang"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiang An"
    },
    {
      "affs": [
        2
      ],
      "name": "Tongling Yuan"
    },
    {
      "affs": [
        1
      ],
      "name": "DongXu Liao"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1b03qv2wrq72a.bib",
  "cited_by": 0,
  "doi": "10.3389/fcell.2026.1971375",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13725581/?tool=EBI",
  "id": "1b03qv2wrq72a",
  "issns": [
    "2296-634X"
  ],
  "landing_url": "https://europepmc.org/article/PMC/PMC13725581",
  "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": [
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "2740|Ferroptosis and cancer prognosis"
    ]
  ],
  "openalex": "W7222982588",
  "pdf_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13725581/pdf/?tool=EBI",
  "pmcid": "PMC13725581",
  "pmid": "42973936",
  "published": "2026-10-19",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/1b03qv2wrq72a.ris",
  "sources": [
    {
      "first_seen": "2026-11-03T15:20:50Z",
      "native_id": "PMC:PMC13725581",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13725581"
    },
    {
      "first_seen": "2026-11-04T12:23:56Z",
      "native_id": "PMC13725581",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fcell.2026.1971375"
    },
    {
      "first_seen": "2026-11-04T15:20:48Z",
      "native_id": "MED:42973936",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42973936"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2740|Ferroptosis and cancer prognosis",
      "subfield": "general"
    }
  ],
  "title": "Hypoxia-induced sulfide:quinone oxidoreductase suppresses ferroptosis and promotes gemcitabine resistance through mitochondrial coenzyme Q reduction in pancreatic ductal adenocarcinoma",
  "title_text": "Hypoxia-induced sulfide:quinone oxidoreductase suppresses ferroptosis and promotes gemcitabine resistance through mitochondrial coenzyme Q reduction in pancreatic ductal adenocarcinoma",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:21:47Z",
  "url": "https://research.draconitic.com/paper/1b03qv2wrq72a",
  "venue": "Frontiers in cell and developmental biology",
  "versions": []
}