Significance IDH1 mutation is a common genetic abnormality in human malignancies, whereas selective therapeutics for IDH1-mutated malignancies remain unavailable. Our present study reveals that IDH1-mutated cancer cells exhibit addiction to Nrf2-governed antioxidative pathways. Blockade of Nrf2 transcriptional activity achieved synergistic lethality with a neomorphic IDH1 mutation. We also showed that triptolide serves as a potent Nrf2 inhibitor, which inhibited Nrf2 transcriptional activity and led to apoptotic changes in IDH1-mutated cells via redox catastrophe. We believe that our findings highlight the broad scope and significance of Nrf2 blockade as a therapeutic strategy and provide an actionable strategy for IDH1-mutated malignancies.