Extracellular vesicles derived from Lactobacillus rhamnosus GG inhibit lung cancer cell invasion and metastasis by regulating ADHFE1 expression to modulate metabolic reprogramming.

Non-Small Cell Lung Cancer (NSCLC) remains a leading cause of cancer-related deaths worldwide, creating an urgent need to explore new drugs and clarify their mechanisms of action. In recent years, lactic acid bacteria-derived extracellular vesicles (EVs) have shown great potential in anti-tumor therapy; however, research on their role in lung cancer remains limited. In this study, EVs from three common Lactobacillus species were isolated to verify their anti-tumor effects on lung cancer. Among these, the extracellular vesicles derived from Lactobacillus rhamnosus GG (LGG-EVs) exhibited the most significant anti-cancer activity. A549 and H1299 cells were treated with LGG-EVs, and transcriptome sequencing analysis was performed. The results revealed that Alcohol Dehydrogenase Iron-Containing 1 (ADHFE1)- a differentially expressed gene with notable changes before and after treatment- displayed the same expression pattern in both cell lines. Further verification was conducted using methods including Western Blotting, Transwell, wound healing, and flow cytometry. Compared with the control group, treatment with LGG-EVs led to downregulated ADHFE1 expression in both cell lines, along with inhibited malignant cellular behaviors and glycolysis capacity. Notably, overexpression of ADHFE1 significantly reversed these effects. These findings indicate that the anti-tumor effect of LGG-EVs on lung cancer may be achieved through ADHFE1-mediated metabolic reprogramming. This study is the first to identify that ADHFE1-mediated metabolic reprogramming could be a key mechanism by which LGG-EVs inhibit lung cancer, providing a new target and strategy for lung cancer treatment.