Icariin Inhibits Lung Adenocarcinoma Progression Through TP53-Mediated Ferroptosis.

Purpose: Lung adenocarcinoma (LUAD) represents the predominant histological subtype of non-small cell lung cancer (NSCLC) and is linked to a diminished overall survival (OS) rate. Icariin (ICA), the principal bioactive compound found in the medicinal plant Epimedium, has demonstrated significant efficacy in inhibiting tumor progression. Ferroptosis, an emerging mechanism of cellular demise, offers a promising avenue for therapeutic intervention in oncology. Nonetheless, the function and modulation of ferroptosis in LUAD are still significantly under-investigated. Methods: A potential ferroptosis target was identified via bioinformatics analysis. Levels of reactive oxygen species (ROS) and ferroptosis-associated markers were quantified, while MTT, wound healing (WH), and Transwell assays were conducted to assess the effect of ICA on the malignant behavior of the LUAD cell line A549. The antitumor activity of ICA was further validated in vivo. Additionally, transcriptome sequencing and bioinformatics analysis were performed to explore ICA-induced molecular regulatory changes associated with the malignant phenotype of tumors. Results: Bioinformatics analysis revealed that TP53 is a potential target of ferroptosis. Cellular experiments demonstrated that ICA induces ferroptosis in a dose-dependent manner, significantly reducing the proliferation, migration, and invasion abilities of A549 cells. Furthermore, the ferroptosis inhibitor Fer-1 can partially reverse both the ferroptosis and the increased expression of TP53 induced by ICA, indicating that ICA suppresses the malignant behavior of A549 cells by inducing TP53-mediated ferroptosis. This mechanism of action was further validated by in vivo experiments. Additional transcriptome sequencing and bioinformatics analysis showed that the mechanism by which ICA inhibits the proliferation of lung cancer cells may be related to its effects on cell cycle and metastasis-related gene sets, lipid metabolism, tumor immune microenvironment, and tumor-promoting pathways, including cholesterol metabolism, cortisol synthesis and secretion, and the PI3K-Akt signaling pathway. Conclusion: ICA demonstrates antitumor properties in LUAD via TP53-mediated ferroptosis, consequently suppressing cellular proliferation.