<p>Osimertinib resistance poses a major challenge in treating advanced EGFR-mutant lung adenocarcinoma (LUAD). Exosomes, key mediators of intercellular communication, may contribute to drug resistance, but their specific role in osimertinib resistance remains unclear. This study aimed to elucidate the function and mechanisms of hypoxia-induced exosomes (HExo) in promoting osimertinib resistance in LUAD, with the goal of identifying potential diagnostic biomarkers and therapeutic targets. Cell survival under osimertinib treatment was analyzed using CCK8 and colony formation assays, while exosomal LUCAT1 was identified via RNA-seq and validated by qRT-PCR. Biological roles of LUCAT1 were assessed through in vitro and in vivo experiments, including immunoblotting, RNA immunoprecipitation (RIP)-qPCR, xenograft tumor models, and organoid models. Results demonstrated that hypoxia-induced exosomal LUCAT1 reduced the sensitivity of recipient LUAD cells to osimertinib. Mechanistically, LUCAT1 promoted osimertinib resistance by preventing c-MET degradation and activating downstream AKT/mTOR and ERK pathways. Targeting c-MET effectively restored osimertinib sensitivity in resistant cells. Moreover, higher levels of exosomal LUCAT1 were significantly associated with poor therapeutic responses to osimertinib in patients. In conclusion, hypoxia-induced exosomal LUCAT1 drives osimertinib resistance by stabilizing c-MET and activating its downstream pathways. Plasma exosomal LUCAT1 levels are closely linked to osimertinib resistance and may serve as an ideal liquid biopsy target for monitoring patient response.</p><p></p>