A novel pyrrolidine-chalcone derivative exhibits synergistic anti-cervical cancer activity by dual-targeting MDM2-p53 axis and ferroptosis pathway

Cervical cancer remains a serious threat to women's health, driving the need for effective and low-toxicity therapeutics. Overall design: In this study, we designed and synthesized a novel series of pyrrolidine-chalcone derivatives targeting the MDM2-p53 interaction. The lead compound, B1, exhibited potent, nanomolar- level cytotoxicity against cervical cancer cells (HeLa/SiHa; IC50 = 0.22/0.24 µM) with minimal toxicity to normal cervical epithelial cells (H8). Mechanistic studies revealed that B1 acts through a novel dual mechanism: it activates the p53 pathway by downregulating MDM2, inducing cell cycle arrest and apoptosis, while simultaneously triggering ferroptosis via reactive oxygen species accumulation, glutathione depletion, and suppression of SLC7A11/ GPX4. These findings identify B1 as a promising dual-mechanism lead compound worthy of further investigation in cervical cancer.