Abstract

Oxaliplatin resistance remains a significant therapeutic challenge in the treatment of colon adenocarcinoma (COAD). In this study, we identified the RNA-binding protein PUM2 as a key driver of oxaliplatin resistance. Bioinformatics analysis revealed that PUM2 was upregulated in tumor tissues, which correlated with poor patient prognosis. Knockdown of PUM2 inhibited cell proliferation and migration and enhanced oxaliplatin sensitivity by promoting ferroptosis. These findings were validated in vivo, where PUM2 knockdown potentiated the anti-tumor efficacy of oxaliplatin in mouse xenograft models. Mechanistically, PUM2 was found to bind to the mRNA of the E3 ubiquitin ligase NEDD4L. Downregulation of NEDD4L reduced the ubiquitination and degradation of the transcription factor NRF2, leading to NRF2 accumulation and inhibiting ferroptosis. Furthermore, combining an NRF2 inhibitor (ML385) with oxaliplatin promoted ferroptosis and suppressed the growth of resistant tumors in vivo. In conclusion, our findings elucidate a novel PUM2/NEDD4L/NRF2 axis that promotes oxaliplatin resistance in COAD by inhibiting ferroptosis, thereby providing a preclinical rationale for future investigation into this pathway to overcome chemoresistance.