LBPs NPs suppress breast cancer progression by inhibiting YAP1 expression to induce ferroptosis and alter energy metabolism

Yes-associated protein 1 (YAP1), a core effector of the Hippo signaling pathway, has garnered increasing attention for its role in ferroptosis signaling in breast cancer. This study investigates the antitumor properties of Lycium barbarum polysaccharides (LBPs) and develops LBPs-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (LBPs NPs), further exploring the mechanisms of free LBPs and LBPs NPs in normal and malignant breast cells. Results demonstrated that YAP1 overexpression drives malignant transformation in normal mammary cells, including aberrant proliferation, apoptosis resistance, cytoskeletal remodeling, and enhanced invasiveness, alongside mitochondrial hyperfunction and altered energy metabolism. However, LBPs effectively suppressed these malignant phenotypes and counteracted the associated mitochondrial and metabolic enhancements by inhibiting YAP1 upregulation. In breast cancer cells, YAP1 overexpression similarly promoted proliferation, invasion, cytoskeletal reorganization, and apoptosis resistance, accompanied by enhanced mitochondrial dysfunction and energy, and acquired ferroptosis resistance. Both LBPs and LBPs NPs significantly inhibited cell proliferation, invasion, and cytoskeletal reorganization, disrupted energy metabolism, and ultimately induced ferroptosis via downregulation of YAP1 expression. Notably, both free LBPs and LBPs NPs effectively suppressed YAP1 expression, with LBPs NPs exhibiting significantly superior efficacy compared to free LBPs. This enhancement is attributed to improved drug delivery efficiency facilitated by the PLGA-based nanocarrier system. Mechanistically, LBPs NPs target the Hippo-YAP1 signaling axis, leading to altered phosphorylation status of YAP1 (p-YAP1), and synergistically induce changes in energy metabolism and ferroptosis to inhibit breast cancer metastasis. These findings provide a proof-of-concept at the in vitro level and a potential nanoparticle-based formulation platform for the treatment of breast cancer.