Decoding phillygenin's dual attack on breast cancer: ferroptosis induction and immune evasion suppression

Ferroptosis and immune evasion are pivotal mechanisms in the pathogenesis of breast Cancer (BC), making them promising therapeutic targets. Phillygenin (PHI), a lignan compound derived from Forsythiae Fructus, has demonstrated broad pharmacological properties, including anti-tumor effects. To discuss the impact of PHI on BC. The study examined PHI's anti-tumor properties and mechanisms using CCK-8 assays, biochemical analyses, DCHF-DA staining, ELISA, immunofluorescence, and western blot techniques. Tumor-bearing mice were utilized for studies in vivo, with tumor tissues being analyzed by H&E staining, immunohistochemistry, and western blotting. The viability of MDA-MB-231 and MCF7 cells was notably repressed by PHI, with respective IC50 values of 81.44 µM and 95.72 µM. PHI elevated intracellular Fe²⁺ levels, an effect synergistically enhanced by erastin but attenuated by ferrostatin-1. Furthermore, PHI increased Reactive Oxygen Species (ROS) levels while downregulating GPX4 and SLC7A11 expression in both cell lines. PHI also enhanced CD8⁺ T cell cytotoxicity and upregulated IFN-γ and IL-2 levels, but suppressing PD-L1 expression. Mechanistically, PHI repressed the phosphorylation of Akt and GSK3β, along with the β-catenin expression, effects that were reversed by the Akt Activator SC79. SC79 also counteracted PHI-induced changes in proliferation, Ferroptosis, and immune evasion markers in MDA-MB-231 cells. PHI decreased tumor size and mass, lowered GPX4, p-AKT/Akt, p-GSK3β/GSK3β, and β-catenin levels, and elevated IFN-γ levels in MDA-MB-231 xenograft models. PHI inhibited BC cell proliferation and immune evasion while promoting Ferroptosis through suppression of the Akt/β-catenin axis, highlighting its possible as a therapeutic agent for BC.