Cholesterol Promotes Lung Adenocarcinoma Brain Metastasis by Stabilizing EGFR Protein to Drive EMT, Metabolic Reprogramming, and Premetastatic Niche Formation

Brain metastasis is a major cause of mortality in advanced lung adenocarcinoma (LUAD). Accumulating evidence indicates that dysregulated lipid metabolism contributes to metastatic colonization; however, how cholesterol functions as a downstream effector within established lipid-metabolic programs to regulate key steps of the LUAD brain metastasis (LUAD-BM) cascade remains incompletely defined. Here, we demonstrate that cholesterol directly engages EGFR and stabilizes its membrane localization by blocking ubiquitin-proteasome-mediated degradation, thereby sustaining AKT/NF-κB signaling. This signaling axis promotes glycolytic reprogramming and epithelial-mesenchymal transition in LUAD cells, enhancing metastatic capacity and resistance to TKIs. Cholesterol also disrupts blood-brain barrier integrity by reducing endothelial membrane fluidity and accelerating Claudin-5 ubiquitination and degradation. Within the brain microenvironment, cholesterol directly interacts with IL-4Rα, facilitating its recruitment into lipid rafts and activation of JAK1/STAT6 signaling, which drives microglial M2 polarization and establishes a permissive pre-metastatic niche. The cholesterol-lowering drug atorvastatin reverses these tumor-intrinsic and microenvironmental effects and suppresses LUAD brain metastasis in vivo. Retrospective clinical analyses further show that hypercholesterolemia is associated with shortened survival in LUAD-BM patients, whereas statin use correlates with improved outcomes. These findings identify cholesterol as a functional mediator downstream of lipid-metabolic dysregulation and therapeutic target in LUAD-BM.