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<p><i>ARID1A</i> is among the most frequently mutated genes in bladder cancer, yet no targeted therapy exists for this molecular subset. Here, we identify ferroptosis induction as a synthetic lethal strategy in <i>ARID1A</i>-deficient bladder cancer. We found that <i>ARID1A</i> loss impaired the NRF2-SLC7A11-glutathione (GSH) axis, leading to redox imbalance and profound sensitivity to the ferroptosis inducer RSL-3. In vitro, <i>ARID1A</i> knockdown depleted intracellular GSH and enhanced RSL-3-induced lipid peroxidation and cell death. Mechanistically, ARID1A directly regulated NRF2 transcription and its target SLC7A11, and restoring SLC7A11 or NRF2 activity or GSH levels rescued ferroptosis sensitivity. In vivo, RSL-3 treatment delayed tumor progression, reduced muscle invasion, and improved survival in two types of <i>Arid1a</i> -deficient mouse models. Furthermore, patient-derived organoids from <i>ARID1A</i>-low human tumors exhibited heightened RSL-3 sensitivity rather than <i>ARID1A</i>-high tumor. Our findings establish ferroptosis as a targetable vulnerability in <i>ARID1A</i>-deficient bladder cancer and provide a compelling rationale for clinical translation of ferroptosis-based therapies in this molecularly defined population.</p><p></p>

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Ferroptosis as a therapeutic vulnerability in ARID1A-deficient bladder cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月10日

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  • Mengxue Zhao,
  • Xuefeng Wang,
  • Xianbin Duan,
  • Chunyue Wu,
  • Rui Guo,
  • Yan Wen,
  • Jiaxin Liang,
  • Jie Zhou,
  • Xuefen Lei,
  • Shi Fu,
  • Haifeng Wang,
  • Cheng Peng,
  • Chunming Guo

摘要

ARID1A is among the most frequently mutated genes in bladder cancer, yet no targeted therapy exists for this molecular subset. Here, we identify ferroptosis induction as a synthetic lethal strategy in ARID1A-deficient bladder cancer. We found that ARID1A loss impaired the NRF2-SLC7A11-glutathione (GSH) axis, leading to redox imbalance and profound sensitivity to the ferroptosis inducer RSL-3. In vitro, ARID1A knockdown depleted intracellular GSH and enhanced RSL-3-induced lipid peroxidation and cell death. Mechanistically, ARID1A directly regulated NRF2 transcription and its target SLC7A11, and restoring SLC7A11 or NRF2 activity or GSH levels rescued ferroptosis sensitivity. In vivo, RSL-3 treatment delayed tumor progression, reduced muscle invasion, and improved survival in two types of Arid1a -deficient mouse models. Furthermore, patient-derived organoids from ARID1A-low human tumors exhibited heightened RSL-3 sensitivity rather than ARID1A-high tumor. Our findings establish ferroptosis as a targetable vulnerability in ARID1A-deficient bladder cancer and provide a compelling rationale for clinical translation of ferroptosis-based therapies in this molecularly defined population.