Objective:To assess the effect of curcumin on CDDP-induced drug resistance and explore the underlying molecular mechanism through Nrf2 system and autophagy pathway. Methods:A drug-resistant cell model was established by exposing A549/CDDP cell to 2 μg/mL CDDP. A549/CDDP cell was treated with 20 μg/mL CDDP and 10 μM cur-cumin. The cell viability and apoptosis level,the signals of Keap1/P62-Nrf2 and auto-phagy pathway were analyzed. Results:CDDP induction promoted drug-resistant phenotype in A549/CDDP cell and activated autophagy as well as Nrf2 signals in A549/CDDP cell. Meanwhile,curcumin combination attenuated autophagy and Nrf2 activation induced by CDDP,and reversed the drug-resistant phenotype. Notably,curcumin combination augmented Keap1 tran-scription. Furthermore,Keap1 ablation with short hairpin RNAs hampered the efficacy of curcumin,suggesting Keap1 played a crucial role on reversal effect of curcumin. Conclusions:The present findings demonstrate that CDDP promotes abnormal activa-tion of Nrf2 pathway and autophagy,leading to drug resistance of A549/CDDP cell. Curcumin attenuates this process and combat drug-resistance through its potent activation on Keap1 transcription,which is essential for interplay between oxidative stress induced Nrf2 activation and autophagy/apoptosis switch.