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In this study, we established a metabolic\u2010mechanotransductive crosstalk wherein cholesterol\u2010driven stromal reprogramming amplifies CRPC progression. Mechanistically, full androgen deprivation (FAD) induces cholesterol metabolic rewiring in prostate cancer (PCa) cells that orchestrates the CH25H\u2010dependent phenotype transformation of cancer\u2010associated fibroblast (CAF) into myofibroblastic CAF (myCAF). In turn, the resulting matrix stiffness induces unfolded protein response (UPR) and potentiates IRE1\u03b1 kinase activity for\n                    <jats:italic>Xbp1<\/jats:italic>\n                    splicing, while concurrently activating the integrin \u03b1V\u03b23\/FAK\/STAT3 axis to transcriptionally replenish\n                    <jats:italic>Xbp1<\/jats:italic>\n                    substrate in PCa cells. This mechanosensitive adaptation thereby confers PCa with resistance to apoptosis induced by FAD. Consequently, pharmacological disruption of this metabolic\u2010mechanotransductive axis by targeting cholesterol metabolism or blockade of IRE1\u03b1\u2010XBP1s signaling significantly suppress tumor growth, representing a promising therapeutic strategy for CRPC progression.\n                  <\/jats:p>","DOI":"10.1002\/advs.75977","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T15:16:19Z","timestamp":1780586179000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cholesterol\u2010Mediated Metabolic\u2010mechanotransductive Crosstalk Orchestrates Castration Resistance in Prostate Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Shaojie","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Urology Xijing Hospital Fourth Military Medical University  Xi'an 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