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Danshensu Ethyl Ester Induces Ferroptosis Through Targeted Inhibition of SLC7A11 Transport Function in NSCLC
Rui Yan1,2, Sen Xu1, Meng Yan3
1Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, China.
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.
Insights
Danshensu Ethyl Ester (DEE) induces cancer cell death by promoting ferroptosis, a cell death pathway. DEE targets SLC7A11, offering potential for non-small cell lung cancer (NSCLC) therapy.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Ferroptosis is an emerging therapeutic target for cancer treatment.
- The therapeutic potential of Danshensu derivatives, including Danshensu Ethyl Ester (DEE), in cancer remains largely unexplored.
- This study investigates the impact of DEE on ferroptosis in non-small cell lung cancer (NSCLC) cells.
Purpose of the Study:
- To investigate the effect of DEE on ferroptosis in NSCLC cells.
- To elucidate the molecular mechanisms underlying DEE-induced ferroptosis.
- To evaluate the in vivo antitumor efficacy of DEE.
Main Methods:
- NSCLC cells were treated with DEE to assess ferroptosis markers (ROS, MDA, GSH, MMP) and related protein expression.
- Molecular docking and dynamics simulations were used to predict the interaction between DEE and SLC7A11.
- In vivo antitumor activity was evaluated using a nude mouse xenograft model.
Main Results:
- DEE treatment dose-dependently induced cell death in NSCLC cells, increasing ROS and MDA, and decreasing GSH and MMP.
- DEE downregulated the expression of SLC7A11 and GPX4, key regulators of ferroptosis.
- DEE directly inhibited SLC7A11 transport function in a p53-independent manner, reducing intracellular cysteine levels and promoting ferroptosis.
Conclusions:
- DEE effectively inhibits NSCLC progression by inducing ferroptosis.
- Targeted inhibition of SLC7A11 transport function by DEE is a key mechanism.
- DEE demonstrates significant potential as a novel therapeutic agent for NSCLC.
