Salidroside induces ferroptosis in breast cancer cells and enhances the anticancer effect of oxaliplatin

Salidroside, derived from Rhodiola rosea as both food and medicine, holds promise in cancer therapy but its efficacy against breast cancer is unknown. This study explored the impact of Rhodiola rosea aqueous extracts (Rre) and salidroside, alone and combined with oxaliplatin, on MDA-MB-231 and MDA-MB-453 breast cancer cells. Based on network pharmacology and bioinformatics, potential mechanism of salidroside on breast cancer focused on the ferroptosis signaling pathway. CCK-8 assays indicated that salidroside inhibits cell proliferation, enhancing oxaliplatin's antitumor effects. qPCR and Western blot analyses revealed decreased SLC7A11 mRNA and protein, reduced GPX4 and GSH levels, and altered GSH, MDA, and Fe contents. Molecular docking and Molecular dynamics simulations results confirmed a strong and stable interaction between SLC7A11 and salidroside. These results suggest that salidroside may induce ferroptosis in breast cancer cells by modulating SLC7A11 and enhance oxaliplatin efficacy, presenting a novel strategy for treating oxaliplatin-resistant triple-negative and HER2-positive breast cancers. • Rhodiola rosea extract inhibits breast cancer growth and enhances oxaliplatin's anticancer effect. • Salidroside, Rhodiola's main active compound, mediates its anticancer and oxaliplatin synergy. • Salidroside can bind to SLC7A11, confirmed by network pharmacology, molecular docking, and molecular dynamics studies. • Salidroside boosts oxaliplatin's effect by blocking SLC7A11-induced ferroptosis, reversible by inhibitors.