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<p>Extracellular matrix (ECM) stiffening and metabolic reprogramming are hallmarks of colorectal cancer (CRC) progression; however, the mechanistic link between biomechanical cues and cholesterol metabolism remains poorly defined. Here, we delineate a mechano-metabolic pathway in which matrix stiffness activates the mechanosensitive Ca²⁺ channel Piezo1 to drive structural reorganization of the Golgi apparatus, promoting its close apposition with the endoplasmic reticulum (ER). This organelle remodeling facilitates the proteolytic activation and nuclear translocation of SREBP2, thereby transcriptionally upregulating HMGCR, the rate-limiting enzyme for cholesterol synthesis, and elevating intracellular cholesterol. HMGCR upregulation is functionally essential for stiffness-induced epithelial-mesenchymal transition (EMT) and CRC progression. Mechanistically, HMGCR-mediated cholesterol accumulation promotes phosphorylation of β-catenin at Ser552, which disrupts β-catenin/E-cadherin complexes at adherens junctions, leading to β-catenin nuclear accumulation and EMT execution. Therapeutically, combined pharmacological inhibition of matrix crosslinking and cholesterol synthesis synergistically suppresses tumor growth and invasion while restoring epithelial architecture in vivo. Collectively, these findings reveal that Piezo1-dependent Golgi-ER reorganization triggers SREBP2-driven cholesterol synthesis, ultimately fueling β-catenin-mediated junctional disassembly and metastasis, and highlight the therapeutic promise of co-targeting tumor mechanics and metabolism.</p>

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Matrix stiffness promotes colorectal cancer progression via Golgi-dependent cholesterol synthesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月24日

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  • Min-Yue Yin,
  • Xue Li,
  • Jun-Qi Zhang,
  • Bo-Shen Lin,
  • Chang-Hao Zhang,
  • Yu-Hang Liu,
  • Shu-Tian Zhang,
  • Si-An Xie

摘要

Extracellular matrix (ECM) stiffening and metabolic reprogramming are hallmarks of colorectal cancer (CRC) progression; however, the mechanistic link between biomechanical cues and cholesterol metabolism remains poorly defined. Here, we delineate a mechano-metabolic pathway in which matrix stiffness activates the mechanosensitive Ca²⁺ channel Piezo1 to drive structural reorganization of the Golgi apparatus, promoting its close apposition with the endoplasmic reticulum (ER). This organelle remodeling facilitates the proteolytic activation and nuclear translocation of SREBP2, thereby transcriptionally upregulating HMGCR, the rate-limiting enzyme for cholesterol synthesis, and elevating intracellular cholesterol. HMGCR upregulation is functionally essential for stiffness-induced epithelial-mesenchymal transition (EMT) and CRC progression. Mechanistically, HMGCR-mediated cholesterol accumulation promotes phosphorylation of β-catenin at Ser552, which disrupts β-catenin/E-cadherin complexes at adherens junctions, leading to β-catenin nuclear accumulation and EMT execution. Therapeutically, combined pharmacological inhibition of matrix crosslinking and cholesterol synthesis synergistically suppresses tumor growth and invasion while restoring epithelial architecture in vivo. Collectively, these findings reveal that Piezo1-dependent Golgi-ER reorganization triggers SREBP2-driven cholesterol synthesis, ultimately fueling β-catenin-mediated junctional disassembly and metastasis, and highlight the therapeutic promise of co-targeting tumor mechanics and metabolism.