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Background <p>Prostate cancer (PCa) exhibits highly heterogeneous clinical outcomes, underscoring the need for biomarkers that more closely reflect tumor biology. While programmed cell death (PCD) is fundamental to tumor suppression, the prognostic impact of individual PCD pathways remains poorly characterized in PCa.</p> Methods <p>We constructed 14 PCD prognostic models in a training cohort (GSE116918, n&#xa0;=&#xa0;248), integrated the top three (apoptosis, entosis, necroptosis) into an AEN score, and validated in two independent cohorts in PCa. Tumor microenvironment (TME), drug sensitivity, single‑cell trajectories, Mendelian randomization, and functional assays were performed.</p> Results <p>The AEN score outperformed single models (AUC&#xa0;=&#xa0;0.857) and independently predicted biochemical recurrence (HR&#xa0;=&#xa0;8.02). High‑AEN tumors exhibited a non‑inflamed TME, predicted immunotherapy resistance, yet increased chemosensitivity. <i>EZR</i> was nominated as a causal driver; knockdown of <i>EZR</i> suppressed proliferation, migration, and tumor growth via YAP/TAZ dysregulation.</p> Conclusions <p>The AEN score is a robust prognostic tool linking PCD activity to PCa aggressiveness and immune evasion. <i>EZR</i> emerges as a functional effector and potential therapeutic target acting through Hippo signaling in PCa.</p>

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An Integrated Cell-Death Program Defines Aggressive Prostate Cancer by Coupling Ezrin to the Hippo–YAP/TAZ Axis

  • 期刊论文

  • 发表日期：

    2026年7月22日

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  • Xing Luo,
  • Zeyu Huang,
  • Min Deng,
  • Jingui Liu,
  • Chaoyu Liao,
  • Youhao Yang,
  • Zhaoyu Meng,
  • Jianxu Yuan,
  • Jiahao Xu,
  • Yuxuan Liu,
  • Qiulin Wang,
  • Zhihao Wang,
  • Hao Li,
  • Ronghui Shi,
  • Han Zeng,
  • Shuai Su,
  • Liang Liu,
  • Ji Zheng

摘要

Background

Prostate cancer (PCa) exhibits highly heterogeneous clinical outcomes, underscoring the need for biomarkers that more closely reflect tumor biology. While programmed cell death (PCD) is fundamental to tumor suppression, the prognostic impact of individual PCD pathways remains poorly characterized in PCa.

Methods

We constructed 14 PCD prognostic models in a training cohort (GSE116918, n = 248), integrated the top three (apoptosis, entosis, necroptosis) into an AEN score, and validated in two independent cohorts in PCa. Tumor microenvironment (TME), drug sensitivity, single‑cell trajectories, Mendelian randomization, and functional assays were performed.

Results

The AEN score outperformed single models (AUC = 0.857) and independently predicted biochemical recurrence (HR = 8.02). High‑AEN tumors exhibited a non‑inflamed TME, predicted immunotherapy resistance, yet increased chemosensitivity. EZR was nominated as a causal driver; knockdown of EZR suppressed proliferation, migration, and tumor growth via YAP/TAZ dysregulation.

Conclusions

The AEN score is a robust prognostic tool linking PCD activity to PCa aggressiveness and immune evasion. EZR emerges as a functional effector and potential therapeutic target acting through Hippo signaling in PCa.