Discovery of novel genipin derivatives as highly selective ferroptosis inducers for the treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is limited in treatment options due to the absence of three receptors, and evidence suggests that TNBC is sensitive to ferroptosis. In this study, a series of genipin derivatives were synthesized through a hybridization strategy that integrated the structures of RSL3 and ML162. Among these derivatives, compound B23 demonstrated remarkable activity against the MDA-MB-231 cell line with an IC50 value of 40 nM, significantly outperforming genipin, RSL3 and ML162. Furthermore, B23 exhibited high selectivity for ferroptosis with a selectivity ratio of up to 108-fold. Further studies revealed that B23 induces ferroptosis by affecting the expression of ferroptosis-related proteins ACSL4, GPX4, and FTH1, thereby disrupting intracellular iron homeostasis and the GSH/GPX4 antioxidant defense system, ultimately leading to the accumulation of lipid peroxidation (LPO). Animal model demonstrated that B23 exhibited potent tumor suppression in an MDA-MB-231 xenograft model, achieving a tumor inhibition rate of 78.46 % at a dose of 4 mg/kg, without observable toxic side effects. In conclusion, B23 represents a promising ferroptosis inducer for the treatment of TNBC and warrants further investigation.