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

  • Adv Sci (Weinh). 2026 Jun 4:e75977. doi: 10.1002/advs.75977.
Shaojie Liu  1 ,  Chao Xu  1 ,  Jun Jiang  1  2 ,  Limin He  1 ,  Yike Zhou  1 ,  Zhengxuan Li  1 ,  Yu Li  3 ,  Keying Zhang  1 ,  Fa Yang  1 ,  Tong Lu  1 ,  Hongtao Song  1 ,  Hai Zhu  1 ,  Zhihao Hu  1 ,  Xiaolong Zhao  1 ,  Kai Gan  1 ,  Hongji Li  1 ,  Bo Yang  1 ,  Rui Zhang  4 ,  Weihong Wen  5 ,  Donghui Han  1 ,  Weijun Qin  1
Affiliations
  • 1. Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
  • 2. Department of Health Service, Base of Health Service, Fourth Military Medical University, Xi'an, China.
  • 3. Department of Urology, Daping Hospital, Army Medical University, Chongqing, China.
  • 4. State Key Laboratory of Cancer Biology, Department of Immunology, Fourth Military Medical University, Xi'an, China.
  • 5. School of Life Science and Technology, Northwestern Polytechnical University, Xi'an, China.
PMID: 42240967 DOI: 10.1002/advs.75977
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.

Keywords
CRPC; cancer associated fibroblast; cholesterol; matrix stiffness; mechanotransduction.
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