Hippo-YAP1 dysregulation contributes to cigarette smoke-induced prostate cancer stemness, reversed by metformin

Prostate cancer (PCa) is the second most diagnosed malignancy in men globally. While large-scale cohort studies report no increase in overall PCa incidence among smokers, cigarette smoke is consistently recognized as a critical risk factor for poorer clinical outcomes and aggressive progression in patients with established PCa, yet the underlying molecular mechanisms remain elusive. Here, we investigate whether Hippo-YAP1 signaling serves as one potential pathway mediating these effects. Through integrative in vitro and in vivo analyses, combined with genetic manipulation of YAP1, we demonstrate that cigarette smoke extract (CSE) induces YAP1 nuclear translocation and upregulates stemness-associated genes (SOX2, CD133, CD44). Genetic manipulation or pharmacological inhibition of YAP1, as well as Hippo pathway activation, mitigates CSE-driven stemness. Crucially, we identify metformin as a modulator of this axis: it enhances Hippo pathway activity, increases YAP1 phosphorylation, and attenuates CSE-induced stemness and tumorigenic potential. Our findings delineate a mechanistic link between smoking and PCa stemness and implicate metformin as a potential agent for targeting smoke-associated cancer progression.