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<p>Targeting mitophagy is a potential strategy to tackle chemoresistance and improve chemotherapy in cancer. Ku80 is reported to play a role in chemoresistance and could exert non-canonical functions in mitophagy, but the mechanism remains largely unknown. Here, we report that increased expression of Ku80 leads to prominent mitophagy in liver cancer cells and tissues. Mechanistically, Ku80 directly regulates Rab7A to enhance formation of mitolysosomes. Elevated cytoplasmic levels of Ku80 and Rab7A in liver cancer tissues correlate with improved disease-free survival (DFS) and overall survival (OS) and significantly enhance the efficacy of adjuvant chemotherapy in surgical liver cancer patients. Several FDA-approved drugs can be repurposed as mitophagy activators, which enhance the chemotherapeutic agent epirubicin and Ku80/Rab7A interactions. Therefore, we have discovered the non-canonical role of Ku80 in mitophagy by directly regulating Rab7A in liver cancer, which is a potentially druggable and molecular subtyping strategy to improve chemotherapy outcomes.</p><p></p>

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Non-canonical role of Ku80 stabilizes Rab7A to enhance mitolysosome formation and chemotherapy in liver cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月3日

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  • Baojia Zou,
  • Lukun Yang,
  • Yihua Dai,
  • Peiping Li,
  • Manyao Zhang,
  • Bailiang He,
  • Jianzhong He,
  • Decheng Li,
  • En Lin,
  • Chaonong Cai,
  • Yiguang Lin,
  • Mingjian Lu,
  • Jian Li

摘要

Targeting mitophagy is a potential strategy to tackle chemoresistance and improve chemotherapy in cancer. Ku80 is reported to play a role in chemoresistance and could exert non-canonical functions in mitophagy, but the mechanism remains largely unknown. Here, we report that increased expression of Ku80 leads to prominent mitophagy in liver cancer cells and tissues. Mechanistically, Ku80 directly regulates Rab7A to enhance formation of mitolysosomes. Elevated cytoplasmic levels of Ku80 and Rab7A in liver cancer tissues correlate with improved disease-free survival (DFS) and overall survival (OS) and significantly enhance the efficacy of adjuvant chemotherapy in surgical liver cancer patients. Several FDA-approved drugs can be repurposed as mitophagy activators, which enhance the chemotherapeutic agent epirubicin and Ku80/Rab7A interactions. Therefore, we have discovered the non-canonical role of Ku80 in mitophagy by directly regulating Rab7A in liver cancer, which is a potentially druggable and molecular subtyping strategy to improve chemotherapy outcomes.