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Salvianolic Acid A Induces Ferroptosis in Non-Small Cell Lung Cancer via the SRC/YAP/GPX4 Axis
Ruyu Jiang1, Haoshu Liu1, Hairong Xiang1
1College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
Abstract:
Lung cancer is the most common malignant tumor worldwide in terms of both incidence and mortality, and the development of highly effective, low-toxicity therapeutic strategies remains an urgent clinical challenge. Here, we report that Salvianolic acid A (SAA), a natural compound extracted from Salvia miltiorrhiza Bunge, inhibits the proliferation of non-small cell lung cancer (NSCLC) cells and induces ferroptosis. Mechanistically, SAA acts as an SRC kinase inhibitor, blocking SRC autophosphorylation at Tyr416, thereby disrupting the SRC-YAP interaction and preventing YAP nuclear translocation. This leads to GPX4 downregulation and subsequently triggers ferroptosis, characterized by increased reactive oxygen species (ROS), Fe2+ accumulation, and lipid peroxidation. Overexpression of YAP abrogates the effects of SAA, while inhibiting SRC or YAP enhances its activity. SAA inhibits tumor growth and downregulates key effector molecules in vivo. In summary, this study reveals a novel mechanism by which SAA induces ferroptosis via the SRC/YAP/GPX4 axis, supporting its further development as a candidate therapeutic agent for NSCLC.
Insights
Salvianolic acid A (SAA) combats non-small cell lung cancer (NSCLC) by inducing ferroptosis. This natural compound inhibits the SRC/YAP/GPX4 pathway, offering a promising therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Lung cancer is a leading cause of cancer mortality globally.
- Developing effective, low-toxicity treatments for non-small cell lung cancer (NSCLC) remains a critical challenge.
Purpose of the Study:
- To investigate the anti-cancer effects of Salvianolic acid A (SAA) on NSCLC.
- To elucidate the molecular mechanism underlying SAA's anti-cancer activity, focusing on ferroptosis induction.
Main Methods:
- In vitro studies using NSCLC cell lines to assess proliferation and ferroptosis markers.
- Western blotting and immunofluorescence to analyze protein expression and localization (SRC, YAP, GPX4).
- In vivo xenograft models to evaluate SAA's efficacy in inhibiting tumor growth.
Main Results:
- SAA significantly inhibits NSCLC cell proliferation and induces ferroptosis, evidenced by increased reactive oxygen species (ROS), Fe2+ accumulation, and lipid peroxidation.
- SAA functions as an SRC kinase inhibitor, blocking SRC autophosphorylation and disrupting the SRC-YAP interaction, thus preventing YAP nuclear translocation.
- Downregulation of GPX4 mediated by SAA is crucial for ferroptosis induction; YAP overexpression rescues SAA's effects.
- SAA treatment suppressed tumor growth and downregulated key effector molecules in vivo.
Conclusions:
- Salvianolic acid A (SAA) represents a novel therapeutic candidate for NSCLC.
- SAA induces cancer cell death through ferroptosis via the SRC/YAP/GPX4 signaling axis.
- Targeting the SRC/YAP/GPX4 pathway with SAA offers a promising strategy for NSCLC treatment.