Salidroside exerts anti-cancer activity in lung adenocarcinoma by inducing ferroptosis through dual inhibition of the SLC7A11/cystine/GSH/GPX4 axis and the AKT/mTORC1/GPX4 pathway

  • Pathol Res Pract. 2026 Aug:284:156510. doi: 10.1016/j.prp.2026.156510.
Huan Wang  1 ,  Yali Cheng  2 ,  Shujun Wu  1 ,  Jiang Shi  3
Affiliations
  • 1. Department of Respiratory Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • 2. Department of Nuclear Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
  • 3. Department of Respiratory Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China. Electronic address: [email protected].
PMID: 42119357 DOI: 10.1016/j.prp.2026.156510
Abstract

Background: Salidroside (Sal), a phenolic compound from Rhodiola Plants, exhibits the anti-tumor potential in various cancers, including lung adenocarcinoma (LUAD). This study is designed to determine whether its mechanism of action involves the specific induction of Ferroptosis in LUAD.

Methods: An integrated suite of computational strategies, including network pharmacology, bioinformatics, and molecular docking, were used to elucidate the functions, targets, and mechanisms of Sal in LUAD. Cell cytotoxicity was assessed by using CCK-8 assay, PI staining, and LDH release assays. Ferroptosis was evaluated by measuring intracellular ROS, Fe2 + , MDA, and lipid ROS. The action mechanism of Sal was examined through metabolite quantification, western blot, and genetic or pharmacological rescue experiments. The involvement of GSH metabolic pathway was specifically examined by quantifying cystine uptake and determining the the levels of cysteine, GSH, and GSH/GSSG. LUAD cell malignant behaviours were examined by colony formation, wound healing, and transwell invasion assays. Western blot was used to determine the levels of SLC7A11, GPX4, and Akt/mTORC1-related protein. Tumor-bearing nude mice were used for exploring the regulation of Sal on LUAD tumorigenicity and Ferroptosis.

Results: Sal induced Ferroptosis to inhibit LUAD cell malignant phenotypes. Sal targeted SLC7A11, disrupting cystine uptake and GSH metabolism, leading to GPX4 inactivation. SLC7A11 overexpression reversed Sal-mediated Ferroptosis and anti-tumor activity. Concurrently, Sal suppressed the Akt/mTORC1 signaling pathway to lower GPX4 protein expression, and mTOR Activator counteracted Sal's efficiency. Sal also prevented mice tumor growth through Ferroptosis induction.

Conclusion: Sal represses LUAD progression by facilitating Ferroptosis through dual inhibition of the SLC7A11/cystine/GSH/GPX4 axis and the Akt/mTORC1/GPX4 pathway. Sal is potentially exploited as a Ferroptosis inducer to treat LUAD.

Keywords
Ferroptosis; GPX4; Lung adenocarcinoma; SLC7A11; Salidroside.
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