Abstract

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. The alternative text for this image may have been generated using AI.