Prostate Club-like Cells Reveal Context-Dependent Epithelial States in Homeostasis Remodeling and Cancer.

Prostate club-like cells have emerged as a recurrent but conceptually unsettled epithelial population across normal prostate, benign remodeling, inflammatory lesions, and prostate cancer. Although the term derives from airway biology, current evidence suggests that, in the prostate, these cells are better viewed as context-dependent noncanonical epithelial states than as a definitive lineage. Single-cell, spatial transcriptomic, and integrative studies place club-like cells most consistently in the prostatic urethra and proximal ducts under near-homeostatic conditions, whereas related programs reappear in benign prostatic hyperplasia, proliferative inflammatory atrophy, and tumor-associated niches. Across these contexts, club-like states intersect with androgen perturbation, inflammatory remodeling, epithelial plasticity, and treatment adaptation. Molecularly, they are defined less by a single marker than by a partially overlapping secretory, stress-associated, and remodeling-related gene program, with variable relationships to urethral luminal, intermediate, and progenitor-like epithelial states. This review synthesizes current evidence on the definition, distribution, molecular identity, functional implications, and disease relevance of prostate club-like cells. We argue that their main significance lies in clarifying prostate epithelial heterogeneity and state transitions, while key priorities include harmonized nomenclature, longitudinal sampling, spatial validation, and functional perturbation.