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<p>Post-translational modifications (PTMs) play a critical role in cancer radioresistance, yet how they regulate ferroptosis to influence radiotherapy response remains poorly understood. Here, we show that HDAC4 promotes radiation resistance in lung cancer by inhibiting ferroptosis. Through a CRISPR screen in patient-derived organoids, we identify HDAC4 as a key mediator. Mechanistically, HDAC4 acts as an E3 SUMO ligase that SUMOylates MBD1, preventing its ubiquitination and degradation. Stabilized MBD1 represses <i>TP53</i> and <i>CYP1A1</i> transcription, thereby suppressing lipid reactive oxygen species formation and ferroptosis. To target HDAC4, we develop a proteolysis-targeting chimera (PROTAC), TP1, based on tasquinimod, which binds and degrades HDAC4 specifically, as confirmed by surface plasmon resonance and proteomics. TP1 exhibits stronger radiosensitizing effects than tasquinimod in lung cancer organoids and xenograft models. Our findings uncover HDAC4 as a suppressor of ferroptosis in radioresistance and present a PROTAC-based strategy to enhance radiotherapy efficacy.</p>

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An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月25日

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  • Chun Cheng,
  • Longhua Sun,
  • Jiaxue Yang,
  • Zhiliang Liu,
  • Fan Zhang,
  • Lingyan Qiu,
  • Meng Yu,
  • Ting Wang,
  • Jianxin Huang,
  • Li Wang,
  • Wei-Ping Min,
  • Tingxiu Xiang,
  • Kaishun Hu,
  • Yi Sang

摘要

Post-translational modifications (PTMs) play a critical role in cancer radioresistance, yet how they regulate ferroptosis to influence radiotherapy response remains poorly understood. Here, we show that HDAC4 promotes radiation resistance in lung cancer by inhibiting ferroptosis. Through a CRISPR screen in patient-derived organoids, we identify HDAC4 as a key mediator. Mechanistically, HDAC4 acts as an E3 SUMO ligase that SUMOylates MBD1, preventing its ubiquitination and degradation. Stabilized MBD1 represses TP53 and CYP1A1 transcription, thereby suppressing lipid reactive oxygen species formation and ferroptosis. To target HDAC4, we develop a proteolysis-targeting chimera (PROTAC), TP1, based on tasquinimod, which binds and degrades HDAC4 specifically, as confirmed by surface plasmon resonance and proteomics. TP1 exhibits stronger radiosensitizing effects than tasquinimod in lung cancer organoids and xenograft models. Our findings uncover HDAC4 as a suppressor of ferroptosis in radioresistance and present a PROTAC-based strategy to enhance radiotherapy efficacy.