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<p>Acquired resistance to enzalutamide (Enz) presents a significant challenge in castration-resistant prostate cancer (CRPC), and overcoming this resistance remains an unmet clinical need. Here, we identified cuproptosis, a copper-dependent mechanism of regulated cell death, as a key driver of Enz resistance. Both in vitro and in vivo models demonstrated that pyruvate dehydrogenase E1 alpha subunit (PDHA1) serves as a critical modulator of cuproptosis and Enz sensitivity. Mechanistically, PDHA1 increases intracellular acetyl-CoA, enhancing histone H3K27 acetylation and upregulating solute carrier family 7 member 11 (SLC7A11), which promotes cysteine uptake and glutathione (GSH) synthesis. Elevated GSH chelates intracellular copper, thereby suppressing cuproptosis and reducing Enz efficacy. Targeting PDHA1 significantly restores cuproptosis and sensitizes CRPC cells to Enz treatment. These findings underscore the potential of PDHA1 inhibition to counteract Enz resistance by reactivating cuproptosis, offering a promising therapeutic approach for treating refractory prostate cancer.</p><p></p>

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PDHA1–acetylation signaling suppresses cuproptosis to attenuate anti-androgen effect in prostate cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月23日

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  • Ruilin Zhuang,
  • Qianghua Zhou,
  • Bisheng Cheng,
  • Shirong Peng,
  • Zhi Xiong,
  • Zhaoxiang Xie,
  • Weilong Lin,
  • Tong Su,
  • Zean Li,
  • Kai Yao,
  • Zhiming Wu,
  • Hai Huang,
  • Kaiwen Li

摘要

Acquired resistance to enzalutamide (Enz) presents a significant challenge in castration-resistant prostate cancer (CRPC), and overcoming this resistance remains an unmet clinical need. Here, we identified cuproptosis, a copper-dependent mechanism of regulated cell death, as a key driver of Enz resistance. Both in vitro and in vivo models demonstrated that pyruvate dehydrogenase E1 alpha subunit (PDHA1) serves as a critical modulator of cuproptosis and Enz sensitivity. Mechanistically, PDHA1 increases intracellular acetyl-CoA, enhancing histone H3K27 acetylation and upregulating solute carrier family 7 member 11 (SLC7A11), which promotes cysteine uptake and glutathione (GSH) synthesis. Elevated GSH chelates intracellular copper, thereby suppressing cuproptosis and reducing Enz efficacy. Targeting PDHA1 significantly restores cuproptosis and sensitizes CRPC cells to Enz treatment. These findings underscore the potential of PDHA1 inhibition to counteract Enz resistance by reactivating cuproptosis, offering a promising therapeutic approach for treating refractory prostate cancer.