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<p>Fibrosis is characterized by excessive extracellular matrix (ECM) deposition driven by mechanical stress, yet the underlying molecular mechanisms remain incompletely understood. To investigate whether mechanical stress–induced ECM remodeling is mediated by YAP/TAZ–TEAD signaling and whether pharmacological modulation can mimic or reverse these effects. Nucleus pulposus (NP) cells were exposed to mechanical stress and treated with the MST1/2 inhibitor XMU-MP-1 or the YAP/TAZ–TEAD inhibitor Verteporfin (VP). Nuclear localization of YAP/TAZ–TEAD, expression of canonical TEAD target genes (CTGF, CYR61, ANKRD1), and ECM markers (Col1, Col2, α-SMA, FN, CTGF) were analyzed by Western blot, qPCR, and immunofluorescence. Mechanical stress induced nuclear accumulation of YAP/TAZ–TEAD, upregulated TEAD target genes, and promoted profibrotic ECM remodeling. XMU-MP-1 recapitulated these effects, while VP suppressed TEAD-dependent transcription and reversed ECM remodeling without affecting nuclear localization. YAP/TAZ–TEAD signaling mediates mechanically induced ECM remodeling. Activation of this pathway drives profibrotic gene expression, and disruption of YAP–TEAD interaction effectively reverses these changes, highlighting a potential therapeutic target for fibrosis.</p>

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In vitro evaluation of Verteporfin and exploration of TEAD palmitoylation inhibition in Piezo1–YAP/TAZ signaling and ECM remodeling

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月17日

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  • Zhuang Xiaojun,
  • Qiyong Chen,
  • Shaoqiang Liu,
  • Boling Liu

摘要

Fibrosis is characterized by excessive extracellular matrix (ECM) deposition driven by mechanical stress, yet the underlying molecular mechanisms remain incompletely understood. To investigate whether mechanical stress–induced ECM remodeling is mediated by YAP/TAZ–TEAD signaling and whether pharmacological modulation can mimic or reverse these effects. Nucleus pulposus (NP) cells were exposed to mechanical stress and treated with the MST1/2 inhibitor XMU-MP-1 or the YAP/TAZ–TEAD inhibitor Verteporfin (VP). Nuclear localization of YAP/TAZ–TEAD, expression of canonical TEAD target genes (CTGF, CYR61, ANKRD1), and ECM markers (Col1, Col2, α-SMA, FN, CTGF) were analyzed by Western blot, qPCR, and immunofluorescence. Mechanical stress induced nuclear accumulation of YAP/TAZ–TEAD, upregulated TEAD target genes, and promoted profibrotic ECM remodeling. XMU-MP-1 recapitulated these effects, while VP suppressed TEAD-dependent transcription and reversed ECM remodeling without affecting nuclear localization. YAP/TAZ–TEAD signaling mediates mechanically induced ECM remodeling. Activation of this pathway drives profibrotic gene expression, and disruption of YAP–TEAD interaction effectively reverses these changes, highlighting a potential therapeutic target for fibrosis.