Discovery of novel thiazolylhydrazone derivatives as potent anti-cancer agents inducing ferroptosis via direct NRF2 inhibition.

Nuclear factor erythroid 2-related factor 2 (NRF2/NFE2L2) is a key transcription factor regulating antioxidant defense and iron metabolism. Its activation confers ferroptosis resistance to cancer cells and promotes tumor progression. In this study, we designed and synthesized a novel series of thiazolylhydrazone derivatives (1a-1g, 2a-2e, and 3a-3i) as NRF2 inhibitors and evaluated their antiproliferative activities against a panel of cancer cell lines. Among them, PhcY emerged as the most potent compound. Molecular docking studies demonstrated its strong binding affinity to the NRF2 active site, indicating direct inhibition. PhcY induced ferroptosis in MCF-7 breast cancer cells via NRF2 inhibition. Mechanistic investigations revealed that PhcY disrupted cellular iron homeostasis, facilitated ferritin degradation, and ultimately triggered ferroptosis. In vivo, PhcY demonstrated significant antitumor efficacy in MCF-7 xenograft-bearing mice at a dose of 10 mg/kg. These findings highlight the potential of thiazolylhydrazone derivatives, particularly PhcY, as NRF2-targeted ferroptosis inducers for cancer therapy.