{
  "abstract": "Background: Ovarian cancer is characterized by an immunosuppressive “cold” tumor microenvironment, which poses a major challenge to effective therapy. Inducing immunogenic cell death through PANoptosis represents a promising strategy for remodeling the tumor microenvironment. Z-DNA binding protein 1 (ZBP1), an interferon (IFN)-stimulated gene, is a key sensor of Z-conformation nucleic acids (Z-NA) driving PANoptosis. While ZBP1 upregulation is traditionally attributed to transcriptional induction, its early non-transcriptional regulatory mechanisms remain elusive.\n\nMethods: ZBP1 expression and its prognostic value were analyzed using public databases and clinical cohorts. APEX2 proximity labeling, PLA and Co-IP identified the E3 ubiquitin ligase regulating ZBP1. The IFN-mediated ZBP1 post-translational modification pathway was delineated utilizing PLA, Co-IP, in vitro phosphorylation, mutagenesis assays, an intestine-specific conditional knockout model. DCAF1−/− ovarian cancer cells and immunocompetent ID8 peritoneal models were generated to evaluate tumor growth and cell death. The therapeutic efficacy of combining the DCAF1 inhibitor (B32B3) with the Z-NA inducer (CBL0137) was assessed in an immunocompetent ID8 murine peritoneal tumor model and two chemoresistant patient-derived xenograft (PDX) models.\n\nResults: ZBP1 is significantly downregulated in ovarian cancer, whereas its elevated expression predicts a favorable prognosis and correlates with high IFN responsiveness. Type I IFN triggers a rapid accumulation of ZBP1 protein prior to its transcriptional upregulation. Mechanistically, we identified the E3 ligase substrate receptor DCAF1 as a negative regulator that targets ZBP1 for proteasomal degradation. Interferon signaling activates the kinase DAPK3, which phosphorylates DCAF1 at S1328. This phosphorylation event compromises the assembly of the CRL4DCAF1 complex, thereby abrogating DCAF1-mediated degradation of ZBP1. In ovarian cancer models, genetic ablation of DCAF1 restored ZBP1 levels and significantly restrained tumor progression. Therapeutically, combining B32B3 with CBL0137 elevated intracellular Z-NA and stabilized ZBP1, driving PANoptosis and suppressing ovarian tumor growth.\n\nConclusions: Our study identifies the IFN-DAPK3-DCAF1 pathway as a critical post-translational mechanism that ensures rapid ZBP1 stabilization. This highlights a fundamental strategy to bypass transcriptional latency for the rapid activation of immune responses, offering a strong clinical rationale to harness this pathway to induce ZBP1-dependent PANoptosis for the treatment of refractory tumors.\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13045-026-01820-8.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China",
    "Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China",
    "Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022 China",
    "Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China",
    "Division of Oncological Sciences, Oregon Health & Science University, Portland, OR 97201 USA",
    "Knight Cancer Institute, Portland, OR 97201 USA"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 18,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Zhiqi Liao"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Linghui Wang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ziyan Zhang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Wenjian Gong"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Mengshi Luo"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yuewen Zhang"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Qiuyang Xu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yijie Wu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Shennan Shi"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Fan Xiong"
    },
    {
      "affs": [
        3
      ],
      "name": "Li Zhu"
    },
    {
      "affs": [
        0,
        1,
        4,
        5
      ],
      "name": "Xuejiao Zhao"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Gordon B. Mills"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ding Ma"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Dan Liu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Guang-Nian Zhao"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Qinglei Gao"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yong Fang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/dfefb0qzmpat0.bib",
  "cited_by": 1,
  "doi": "10.1186/s13045-026-01820-8",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13729483/",
  "id": "dfefb0qzmpat0",
  "issns": [
    "1756-8722"
  ],
  "landing_url": "https://doi.org/10.1186/s13045-026-01820-8",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "2403|interferon and immune responses"
    ]
  ],
  "openalex": "W7166075354",
  "pdf_url": null,
  "pmcid": "PMC13729483",
  "pmid": "42363283",
  "published": "2026-06-26",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/dfefb0qzmpat0.ris",
  "sources": [
    {
      "first_seen": "2026-11-07T12:22:14Z",
      "native_id": "PMC13729483",
      "source": "pmc",
      "url": "https://doi.org/10.1186/s13045-026-01820-8"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|interferon and immune responses",
      "subfield": "immunology"
    }
  ],
  "title": "The DAPK3-DCAF1 pathway regulates ZBP1 protein stability to orchestrate PANoptosis for ovarian cancer therapy",
  "title_text": "The DAPK3-DCAF1 pathway regulates ZBP1 protein stability to orchestrate PANoptosis for ovarian cancer therapy",
  "type": "peer-reviewed",
  "updated_at": "2026-11-07T12:22:14Z",
  "url": "https://research.draconitic.com/paper/dfefb0qzmpat0",
  "venue": "Journal of Hematology & Oncology",
  "versions": []
}