{
  "abstract": "Ovarian cancer remains the leading cause of gynecologic cancer mortality, yet nearly half of BRCA1/2-mutated ovarian cancer patients eventually develop resistance to poly(ADP-ribose) polymerase (PARP) inhibitors. In this study, we investigated whether lixumistat, a novel oxidative phosphorylation (OXPHOS) inhibitor, could overcome PARP inhibitor resistance in preclinical BRCA1/2-mutated ovarian cancer models. Long-term olaparib exposure generated olaparib-resistant BRCA-mutated ovarian cancer cell lines and patient-derived tumor xenograft (PDTX) models. Olaparib-resistant cells exhibited elevated OXPHOS activity. Lixumistat, when combined with olaparib, demonstrated synergistic antitumor effects in both olaparib-sensitive and -resistant cell lines and PDTX models. Switching from olaparib monotherapy to combination markedly suppressed tumor growth in partially resistant and acquired-resistant PDTX models. These results suggest that early integration of lixumistat could enhance efficacy and delay PARP inhibitor resistance. Mechanistically, lixumistat restores PARP inhibitor sensitivity by inhibiting the OXPHOS–NAD⁺-poly(ADP)-ribosylation (PARylation) axis, which reduces NAD⁺ availability and subsequent PARylation. Exogenous NAD⁺ reversed these effects. Additionally, lixumistat downregulated the SNAIL-mediated IL6-phosphorylated STAT3 and phosphorylated retinoblastoma pathway, impairing cell-cycle progression and further enhancing PARP inhibitor efficacy. Together, these findings identify a novel OXPHOS-associated mechanism underlying PARP inhibitor resistance and establish lixumistat as a promising combinatorial strategy to potentiate PARP inhibitors in both PARP inhibitor-naive and -resistant ovarian cancer.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Biomedical Science, The Graduate School, CHA University, Seongnam-si, Republic of Korea",
    "Hematology and Oncology, CHA Bundang Medical Center, CHA University, Seongnam-si, Republic of Korea"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Sa Deok Hong"
    },
    {
      "affs": [
        0
      ],
      "name": "Nar Bahadur Katuwal"
    },
    {
      "affs": [
        0
      ],
      "name": "Mithun Ghosh"
    },
    {
      "affs": [
        0
      ],
      "name": "Seong Min Park"
    },
    {
      "affs": [
        0
      ],
      "name": "Ju Hyun Kim"
    },
    {
      "affs": [
        1
      ],
      "name": "Seul-Gi Kim"
    },
    {
      "affs": [
        0
      ],
      "name": "Min Sil Kang"
    },
    {
      "affs": [
        1
      ],
      "name": "Yong Wha Moon",
      "orcid": "0000-0002-7943-974X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/95zf6wm67y1dv.bib",
  "cited_by": 0,
  "doi": "10.1038/s41419-026-09140-y",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13737184/",
  "id": "95zf6wm67y1dv",
  "issns": [
    "2041-4889"
  ],
  "landing_url": "https://doi.org/10.1038/s41419-026-09140-y",
  "language": "en",
  "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",
      "Article"
    ],
    [
      "openalex",
      "2730|PARP inhibition in cancer therapy"
    ]
  ],
  "openalex": "W7201886341",
  "pdf_url": "https://www.nature.com/articles/s41419-026-09140-y_reference.pdf",
  "pmcid": "PMC13737184",
  "pmid": "42982784",
  "published": "2026-08-07",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/95zf6wm67y1dv.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T12:22:27Z",
      "native_id": "PMC13737184",
      "source": "pmc",
      "url": "https://doi.org/10.1038/s41419-026-09140-y"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|PARP inhibition in cancer therapy",
      "subfield": "oncology"
    }
  ],
  "title": "Targeting oxidative phosphorylation with lixumistat overcomes PARP inhibitor resistance in ovarian cancer",
  "title_text": "Targeting oxidative phosphorylation with lixumistat overcomes PARP inhibitor resistance in ovarian cancer",
  "type": "peer-reviewed",
  "updated_at": "2026-11-09T12:22:27Z",
  "url": "https://research.draconitic.com/paper/95zf6wm67y1dv",
  "venue": "Cell Death & Disease",
  "versions": []
}