Danshensu Ethyl Ester Induces Ferroptosis Through Targeted Inhibition of SLC7A11 Transport Function in NSCLC.

[BACKGROUND] Ferroptosis is a novel research avenue for cancer therapy. The roles of Danshensu derivatives remain unclear. This study investigated the effect of Danshensu Ethyl Ester (DEE) on ferroptosis in non-small cell lung cancer (NSCLC) cells.

[METHODS] NSCLC cells were treated with DEE to assess ferroptosis markers, including reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH), and mitochondrial membrane potential (MMP), along with related protein expression. Molecular docking and dynamics simulations predicted the DEE-SLC7A11 interaction. Intracellular cysteine levels were quantified by ELISA. The functional involvement of SLC7A11 was further verified through its knockdown and overexpression. The in vivo antitumor activity of DEE was assessed using a nude mouse xenograft model.

[RESULTS] DEE treatment dose-dependently promoted cell death in A549 and H1299 cells, accompanied by increased levels of ROS and MDA, reduced GSH and MMP, and downregulated expression of SLC7A11 and GPX4. These effects were reversed by ferroptosis inhibitor Ferrostatin-1 (Fer-1), confirming ferroptosis involvement. Mechanistically, DEE directly inhibited the transport function of SLC7A11 in a p53-independent manner and also decreased p53 protein levels in wild-type A549 cells. Consistently, DEE reduced intracellular cysteine content. Genetic silencing of SLC7A11 enhanced DEE-induced ferroptosis, whereas its overexpression attenuated the effect. In vivo, DEE significantly suppressed tumor growth in a xenograft model, exhibiting efficacy comparable to that of paclitaxel.

[CONCLUSIONS] DEE inhibits NSCLC progression by inducing ferroptosis through the targeted inhibition of SLC7A11 transport function via a p53-independent pathway, highlighting its potential as a novel therapeutic agent for NSCLC.