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<p>Despite significant advances in the treatment of non-small cell lung cancer (NSCLC), acquired resistance remains a major obstacle in advanced stages. Elucidating the molecular mechanisms underlying resistance is crucial for improving clinical outcomes, overcoming therapeutic limitations, and developing effective combination strategies. Here, we identify TRIM25 as a key driver of tumor progression and chemoresistance by promoting the destabilization of AGO2. Mechanistically, TRIM25 directly binds to AGO2 and induces its polyubiquitination, triggering proteasomal degradation. This process downregulates miR-148b-5p, a tumor-suppressive miRNA that post-transcriptionally represses ABCC1 to counteract chemoresistance. Knockdown of TRIM25 restores AGO2 stability by attenuating ubiquitination, thereby reinstating miR-148b-5p-mediated suppression of ABCC1. Functionally, the TRIM25–AGO2–miR-148b-5p–ABCC1 axis inhibits tumor growth and re-sensitizes NSCLC cells to chemotherapy. Notably, therapeutic delivery of miR-148b-5p mimics robustly suppresses NSCLC progression and overcomes chemoresistance in cell lines, xenografts, and patient-derived xenograft (PDX) models, highlighting its translational potential. Our study unveils a previously unrecognized regulatory axis governing chemoresistance in NSCLC, providing both mechanistic insights and novel therapeutic avenues to combat treatment resistance.</p><p></p>

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Targeting the TRIM25–AGO2–miR-148b-5p–ABCC1 axis overcomes chemoresistance in non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月30日

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  • Zihan Zhou,
  • Ran Chen,
  • Lian Li,
  • Runhui Lu,
  • Hongyan Li,
  • Junya Li,
  • Yingting Cao,
  • Yixin Zhang,
  • Xiangling Jiang,
  • Anan Xu,
  • Yun Yi,
  • Yanli Wang,
  • Jian Huang,
  • Xiaojing Zhao,
  • Chunling Du,
  • Jianxiu Yu

摘要

Despite significant advances in the treatment of non-small cell lung cancer (NSCLC), acquired resistance remains a major obstacle in advanced stages. Elucidating the molecular mechanisms underlying resistance is crucial for improving clinical outcomes, overcoming therapeutic limitations, and developing effective combination strategies. Here, we identify TRIM25 as a key driver of tumor progression and chemoresistance by promoting the destabilization of AGO2. Mechanistically, TRIM25 directly binds to AGO2 and induces its polyubiquitination, triggering proteasomal degradation. This process downregulates miR-148b-5p, a tumor-suppressive miRNA that post-transcriptionally represses ABCC1 to counteract chemoresistance. Knockdown of TRIM25 restores AGO2 stability by attenuating ubiquitination, thereby reinstating miR-148b-5p-mediated suppression of ABCC1. Functionally, the TRIM25–AGO2–miR-148b-5p–ABCC1 axis inhibits tumor growth and re-sensitizes NSCLC cells to chemotherapy. Notably, therapeutic delivery of miR-148b-5p mimics robustly suppresses NSCLC progression and overcomes chemoresistance in cell lines, xenografts, and patient-derived xenograft (PDX) models, highlighting its translational potential. Our study unveils a previously unrecognized regulatory axis governing chemoresistance in NSCLC, providing both mechanistic insights and novel therapeutic avenues to combat treatment resistance.