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

ABSTRACT 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.