Abstract:

Triple-negative breast cancer (TNBC) is an aggressive cancer subtype with limited targeted therapies, making ferroptosis a promising therapeutic vulnerability. This study investigates the anti-cancer mechanism of the natural stilbenoid isorhapontigenin (ISO) and its combination efficacy with the ferroptosis sensitizer iFSP1 in human (MDA-MB-231) and murine (4T1) TNBC cells. ISO alone demonstrated strong dose-dependent cytotoxicity in both TNBC lines. Combination treatment of ISO with a non-lethal dose of iFSP1 resulted in a significant synergistic reduction in cell viability (p < 0.001). Mechanistically, ISO acted as a ferroptosis inducer by dramatically upregulating the oxidative stress marker Heme Oxygenase-1 (HO-1). However, the CHX chase assay revealed a novel compensatory effect: ISO also promoted FSP1 protein stability. This suggests the cells attempt to activate an anti-ferroptotic defense to counter the ISO-induced stress. The observed synergy thus results from ISO generating overwhelming damage while iFSP1 disables this FSP1-mediated cellular defense. These findings support using ISO and iFSP1 as a combination therapy to exploit the unique vulnerability of TNBC to ferroptotic cell death.

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