Targeting <i>FOXE1</i> -Mediated LAMC2 Expression to Improve Preoperative Chemoradiotherapy Outcomes in Lung Cancer Patients at Risk of Brain Metastasis

<b><i>Objective:</i></b> This study elucidated the role of the forkhead box E1 (<i>FOXE1</i>)-laminin γ2 (LAMC2) signaling axis in promoting brain metastasis (BM) of lung cancer and evaluated its potential as a therapeutic target to enhance the efficacy of preoperative chemoradiotherapy (CRT). <b><i>Methods:</i></b> Bioinformatics analysis of the GSE126548 dataset revealed a significant association between elevated <i>FOXE1</i> expression and BM in lung cancer patients. Functional <i>in vitro</i> assays-including real-time polymerase chain reaction, Western blotting, migration, invasion, and endothelial permeability assays-were conducted in lung cancer cells and human umbilical vein endothelial cells exposed to tumor-conditioned media. In addition, <i>in vivo</i> xenograft and BM mouse models were established to assess the impact of <i>FOXE1</i> on tumor growth, metastatic potential, and treatment responsiveness. <b><i>Results:</i></b> <i>FOXE1</i> knockdown significantly inhibited lung cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition. Mechanistically, LAMC2 was identified as a downstream effector of <i>FOXE1</i>, with rescue experiments confirming that the <i>FOXE1</i>-LAMC2 axis plays a central role in driving tumor progression and brain metastatic potential. Notably, <i>FOXE1</i> silencing enhanced sensitivity to CRT in preclinical models. <b><i>Conclusions:</i></b> <i>FOXE1</i> promotes lung cancer progression and BM by upregulating LAMC2. Targeting the <i>FOXE1</i>-LAMC2 pathway may improve the efficacy of preoperative CRT and offers a promising strategy for therapeutic intervention in lung cancer patients at high risk of BM.