Canonical Wnt signaling in the regulation of prostate cancer stem cells: a key driver of castration-resistant prostate cancer and a therapeutic opportunity.

Prostate cancer (PCa) is the second leading cause of cancer-related death among men worldwide. Although androgen deprivation therapy (ADT) effectively suppresses tumor growth, most patients eventually progress to castration-resistant prostate cancer (CRPC) and develop metastatic disease. The self-renewal, lineage plasticity, epithelial-mesenchymal transition (EMT), and bone metastatic capacity of prostate cancer stem cells (PCSCs) are central drivers of CRPC progression, therapeutic resistance, and metastasis, and the aberrant activation of the canonical Wnt signaling pathway plays a key regulatory role in this process. This review systematically discusses PCSC markers and their applications in clinical diagnosis, elucidates the molecular mechanisms by which aberrant activation of the canonical Wnt signaling pathway, induced by the synergistic effects of genetic mutations, non-coding RNA (ncRNA) dysregulation, epigenetic dysregulation, tumor microenvironment (TME) alterations, and synergistic crosstalk with androgen receptor (AR) signaling, PI3K/AKT/mTOR signaling, Hippo-YAP/TAZ signaling, and metabolic reprogramming, enhances the stemness of PCSCs and promotes their EMT and bone metastasis. We also summarize current research on therapeutic agents targeting the canonical Wnt signaling pathway to suppress PCSCs, along with major challenges in clinical translation and potential strategies to overcome them. Collectively, we propose that targeting this pathway to inhibit PCSCs represents a highly promising strategy for controlling CRPC progression, overcoming therapeutic resistance, and ultimately improving patient outcomes.