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

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.