Scholarlink

Background <p>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.</p> Methods <p>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. <i>DCAF1</i><sup><i>−/−</i></sup> 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.</p> Results <p>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 CRL4<sup>DCAF1</sup> 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 across.</p> Conclusions <p>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.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

The DAPK3-DCAF1 pathway regulates ZBP1 protein stability to orchestrate PANoptosis for ovarian cancer therapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年6月26日

查看全文
  • Zhiqi Liao,
  • Linghui Wang,
  • Ziyan Zhang,
  • Wenjian Gong,
  • Mengshi Luo,
  • Yuewen Zhang,
  • Qiuyang Xu,
  • Yijie Wu,
  • Shennan Shi,
  • Fan Xiong,
  • Li Zhu,
  • Xuejiao Zhao,
  • Gordon B. Mills,
  • Ding Ma,
  • Dan Liu,
  • Guang-Nian Zhao,
  • Qinglei Gao,
  • Yong Fang

摘要

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.

Methods

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.

Results

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 across.

Conclusions

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.