Cellular senescence and benign prostatic hyperplasia: the pathological role of the senescence-associated secretory phenotype and the translational potential of senolytics

Benign prostatic hyperplasia (BPH) is a common urological disease among older men, and its development and progression are closely associated with aging. However, existing theories involving androgens, chronic inflammation, and epithelial–stromal interactions cannot fully explain the pronounced age dependence of BPH. In recent years, cellular senescence, a stable state of cell-cycle arrest, has attracted increasing attention. Although senescent cells lose their capacity for sustained proliferation, they can develop a senescence-associated secretory phenotype (SASP) and release various pro-inflammatory cytokines, chemokines, growth factors, and extracellular matrix-remodeling molecules, thereby continuously altering the local tissue microenvironment. Existing studies have identified senescence-related changes, including p16^INK4a, p21, SA-β-gal, and telomere shortening, in BPH tissues, suggesting that senescent cells may participate in local prostatic inflammation, epithelial–stromal interactions, and matrix remodeling. However, most current evidence is derived from tissue association studies and in vitro experiments, and the direct causal role of cellular senescence in BPH remains to be further validated. Based on the finding that senescent cells are selectively dependent on specific pro-survival and anti-apoptotic pathways, senolytics, which selectively induce the death of senescent cells, provide a new therapeutic approach for intervening in senescent cell-mediated pathological microenvironments. Dasatinib plus quercetin (D + Q), fisetin, navitoclax, and HSP90 inhibitors have demonstrated some senolytic activity in various models of age-related diseases, but direct pharmacodynamic and clinical efficacy evidence in BPH remains very limited. Therefore, this article reviews evidence for cellular senescence in BPH tissues, SASP-mediated mechanisms of inflammation and proliferation, the senescence–inflammation–proliferation positive-feedback network, and the potential therapeutic mechanisms of senolytics, with particular emphasis on current evidence gaps, targeted drug delivery, safety, and challenges in clinical translation, with the aim of providing a theoretical basis for further research on senescence-targeted strategies in BPH.