ZEB1 orchestrates cellular plasticity and therapy resistance in prostate cancer: From molecular mechanisms to clinical targeting.

Prostate cancer (PCa) is a leading cause of male cancer mortality worldwide. Its treatment failure is predominantly driven by the transition to castration-resistant phenotype (CRPC). Zinc finger E-box binding homeobox 1 (ZEB1) is a master inducer of epithelial-mesenchymal transition and has emerged as a central orchestrator of malignant phenotype. This review clarifies the complex interplay between ZEB1 and the tumor microenvironment, epigenetic modifications, and non-coding RNAs (lncRNAs and miRNAs), highlighting how these interactions collectively drive the progression of PCa. Moreover, ZEB1 is critical in driving the transformation of cancer cells to cancer stem cells and promoting neuroendocrine differentiation. This review highlights ZEB1 to resistance against standard-of-care treatments (such as taxane-based chemotherapies and next-generation androgen receptor pathway inhibitors) by metabolic reprogramming and modulation of androgen receptor signaling. Finally, it explores strategies to disrupt the regulatory circuitry of ZEB1 to overcome multidrug resistance, with the specific aim of evaluating whether ZEB1 can serve as a viable clinical biomarker and therapeutic target for PCa treatment.