eIF4E2 deficiency translationally unleashes WRN to sustain DNA repair-mediated chemoresistance.

Therapeutic resistance to DNA-damaging agents (DDAs) remains a primary obstacle in non-small cell lung cancer (NSCLC) treatment. Through multi-level analyses of clinical cohorts, cell lines, and derived resistant models, we identify eIF4E2 as a promising predictor of resistance to diverse DDAs. Using cisplatin as a model DDA, we find that eIF4E2 deficiency enhances DNA repair and promotes chemoresistance. Mechanistically, eIF4E2 represses translation of the DNA repair helicase WRN by recruiting the miRISC/CCR4-NOT complex to its 3'UTR via hsa-miR-130b-3p/301b-3p. Loss of eIF4E2 relieves WRN translation repression, potentiating DNA repair and attenuating DDA-induced DNA damage. Furthermore, combining the WRN inhibitor HRO761 with cisplatin enhances cytotoxicity in cisplatin-resistant cells. Collectively, these results establish that low eIF4E2 and high WRN levels predict chemoresistance, and that targeting WRN is a promising strategy to overcome cisplatin resistance in NSCLC.