{
  "abstract": "Cytotoxic chemotherapy typically results in the elimination of a fraction of the tumor with surviving cells entering a state of persistence or premature replicative senescence that can lead to recurrence. Here, we show that therapy-induced senescence is associated with robust up-regulation of Fas and/or TRAIL-R2/DR5 death receptors in vitro and in vivo. The latter receptors restricted entry to senescence and exerted selective pressure on senescent cells through promoting assembly of proapoptotic receptor-interacting protein kinase 1 (RIPK1)/Fas-associated death domain protein (FADD)/Caspase-8 \"FADDosome\" complexes, restrained by cFLIPL. Accordingly, deletion of CASP-8 robustly enhanced entry to senescence and prolonged the life span of senescent cells. cIAP-2, which inhibits death receptor-driven cell death, was also up-regulated in senescent cells, and deletion of IAPs suppressed entry to senescence. Consistent with this, small-molecule IAP antagonists exhibited potent senolytic activity through enhancing death receptor-initiated Caspase-8 activation. Thus, death receptor-driven assembly of RIPK1/FADD/Caspase-8 complexes in senescent cells orchestrates addiction to IAPs that can be exploited by IAP antagonists.",
  "abstract_shown": true,
  "affiliations": [
    "Molecular Cell Biology Laboratory, Dept. of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.",
    "Institute for Molecular Immunology, University of Cologne, Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.",
    "Olivia Newton-John Cancer Research Institute, Heidelberg, VIC 3084, Australia.",
    "School of Cancer Medicine, La Trobe University, Melbourne, VIC 3086, Australia.",
    "BioFrontiers Institute, University of Colorado, Boulder, CO 80303, USA.",
    "La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3086 Australia.",
    "Neurovascular Genetics Unit, Dept. of Genetics, The Smurfit Institute, Trinity College, Dublin 2, Ireland.",
    "Dept. of Clinical Medicine and Trinity College Institute of Neuroscience, Trinity College, Dublin 2, Ireland."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Gokhan Gunay",
      "orcid": "0009-0004-5621-5286"
    },
    {
      "affs": [
        0
      ],
      "name": "Seren Hamsici",
      "orcid": "0000-0002-4464-6052"
    },
    {
      "affs": [
        0
      ],
      "name": "Vaishnavi Venugopalan",
      "orcid": "0000-0001-6772-6787"
    },
    {
      "affs": [
        0
      ],
      "name": "Aoife Costigan"
    },
    {
      "affs": [
        1
      ],
      "name": "Melanie Fritsch",
      "orcid": "0000-0003-2699-8860"
    },
    {
      "affs": [
        0
      ],
      "name": "Aislinn Gallagher Aldave"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Anne Huber"
    },
    {
      "affs": [
        4
      ],
      "name": "Brianna Fernandez"
    },
    {
      "affs": [
        0
      ],
      "name": "Hande Efe-Cicek"
    },
    {
      "affs": [
        0
      ],
      "name": "Pavel Davidovich",
      "orcid": "0000-0003-1938-297X"
    },
    {
      "affs": [
        2,
        3,
        5
      ],
      "name": "Pavitha Parathan",
      "orcid": "0009-0005-8991-3061"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Akash Srivaths"
    },
    {
      "affs": [
        6
      ],
      "name": "Natalie Hudson"
    },
    {
      "affs": [
        6
      ],
      "name": "Eleanor Noone",
      "orcid": "0000-0003-4674-7508"
    },
    {
      "affs": [
        6
      ],
      "name": "Jeffrey O’Callaghan",
      "orcid": "0000-0001-8818-4331"
    },
    {
      "affs": [
        2,
        3,
        5
      ],
      "name": "Lisa A. Mielke",
      "orcid": "0000-0002-9522-9320"
    },
    {
      "affs": [
        7
      ],
      "name": "Sarah L. Doyle",
      "orcid": "0000-0002-6294-9380"
    },
    {
      "affs": [
        4
      ],
      "name": "Sabrina L. Spencer",
      "orcid": "0000-0002-5798-3007"
    },
    {
      "affs": [
        6
      ],
      "name": "Matthew Campbell",
      "orcid": "0000-0003-3325-240X"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Conor J. Kearney"
    },
    {
      "affs": [
        1
      ],
      "name": "Hamid Kashkar",
      "orcid": "0000-0003-2796-1429"
    },
    {
      "affs": [
        0
      ],
      "name": "Seamus J. Martin",
      "orcid": "0000-0002-8539-3143"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/72jn5fpmx05tw.bib",
  "cited_by": 0,
  "doi": "10.1126/sciadv.aed4541",
  "fulltext_url": "https://europepmc.org/articles/PMC13693669",
  "id": "72jn5fpmx05tw",
  "issns": [
    "2375-2548"
  ],
  "landing_url": "https://www.science.org/doi/10.1126/sciadv.aed4541",
  "language": "eng",
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Cell death mechanisms and regulation"
    ]
  ],
  "openalex": "W7223321968",
  "pdf_url": "https://europepmc.org/articles/PMC13693669?pdf=render",
  "pmcid": "PMC13693669",
  "pmid": "42912996",
  "published": "2026-10-23",
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "ris": "https://research.draconitic.com/paper/72jn5fpmx05tw.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:41Z",
      "native_id": "10.1126/sciadv.aed4541",
      "source": "crossref",
      "url": "https://www.science.org/doi/10.1126/sciadv.aed4541"
    },
    {
      "first_seen": "2026-10-30T12:20:03Z",
      "native_id": "MED:42912996",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42912996"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Cell death mechanisms and regulation",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Death receptors regulate entry to therapy-induced senescence and orchestrate addiction to IAPs",
  "title_text": "Death receptors regulate entry to therapy-induced senescence and orchestrate addiction to IAPs",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:03Z",
  "url": "https://research.draconitic.com/paper/72jn5fpmx05tw",
  "venue": "Science Advances",
  "versions": []
}