Metabolic Intervention Nanoparticles for Triple‐Negative Breast Cancer Therapy via Overcoming FSP1‐Mediated Ferroptosis Resistance
Jie Yang, Zengguang Jia, Jun Zhang, Xiuhua Pan, Yawen Wei, Siyu Ma, Ning Yang, Zengyi Liu, Qi Shen
Abstract
Triple-negative breast cancer (TNBC) patients have a predisposition to poor prognosis due to the strong malignancy. Ferroptosis, a new form of cell death, is a candidate treatment for TNBC owing to its effectiveness in killing cancer cells. However, some TNBC cells exhibit an abnormal tumor metabolism, especially the ferroptosis suppressor protein 1 (FSP1)-mediated ubiquinone redox metabolism, which can promote ferroptosis resistance. Here, rosuvastatin (RSV) is encapsulated in silk fibroin (SF) nanoparticle (designated as Cu-SF(RSV) NPs) for TNBC inhibition by overcoming FSP1-mediated ferroptosis resistance. RSV intervenes in metabolic mevalonate pathway to disturb the redox homeostasis regulated by CoQ/FSP1 axis, thereby overcoming ferroptosis resistance. Besides, Cu-SF(RSV) NPs can generate reactive oxygen species and deplete glutathione to facilitate redox stress, thereby amplifying ferroptosis effect. Thus, it is anticipated that the metabolic intervention nanoparticles, Cu-SF(RSV) NPs, can be exploited as a promising therapeutic platform for clinical TNBC treatment.