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

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.