Cholesterol‐Mediated Metabolic‐mechanotransductive Crosstalk Orchestrates Castration Resistance in Prostate Cancer

ABSTRACT Biophysical microenvironment fuels therapeutic resistance, yet the contribution of matrix stiffness to castration‐resistant prostate cancer (CRPC) remains poorly understood. In this study, we established a metabolic‐mechanotransductive crosstalk wherein cholesterol‐driven stromal reprogramming amplifies CRPC progression. Mechanistically, full androgen deprivation (FAD) induces cholesterol metabolic rewiring in prostate cancer (PCa) cells that orchestrates the CH25H‐dependent phenotype transformation of cancer‐associated fibroblast (CAF) into myofibroblastic CAF (myCAF). In turn, the resulting matrix stiffness induces unfolded protein response (UPR) and potentiates IRE1α kinase activity for Xbp1 splicing, while concurrently activating the integrin αVβ3/FAK/STAT3 axis to transcriptionally replenish Xbp1 substrate in PCa cells. This mechanosensitive adaptation thereby confers PCa with resistance to apoptosis induced by FAD. Consequently, pharmacological disruption of this metabolic‐mechanotransductive axis by targeting cholesterol metabolism or blockade of IRE1α‐XBP1s signaling significantly suppress tumor growth, representing a promising therapeutic strategy for CRPC progression.