MZT2A drives epithelial-mesenchymal transition in lung adenocarcinoma via the LGALS3BP/ITGB1/TGF-β/smad2 axis.

The high mortality of lung adenocarcinoma (LUAD) is largely attributed to its metastatic propensity; therefore, elucidating novel mechanisms driving metastasis is crucial for developing diagnostic and therapeutic strategies. This study aimed to elucidate the function and mechanism of MZT2A in the metastasis of LUAD. Analysis of clinical samples and public databases revealed that MZT2A is highly expressed in LUAD tissues and significantly associated with lymph node metastasis, advanced stage, and poor prognosis. In vitro functional assays revealed that MZT2A overexpression significantly enhanced the invasion, migration, and adhesion of LUAD cells and induced epithelial-mesenchymal transition (EMT). Mechanistically, via its MOZART2 domain, MZT2A interacts with the SRCR domain of galectin-3-binding protein (LGALS3BP), promoting the sorting of LGALS3BP into exosomes and its subsequent secretion. Secretory LGALS3BP acts as a ligand, binding to integrin beta-1 (ITGB1) on the cell membrane through its BTB domain, thereby activating the downstream TGF-β/smad2 signaling pathway to drive EMT and metastatic phenotypes. Molecular docking and mutation experiments confirmed these critical domain interactions. In vivo experiments also validated that MZT2A overexpression promoted pulmonary metastasis, while LGALS3BP knockdown reversed this effect. Collectively, this study elucidated a novel "MZT2A-LGALS3BP-ITGB1-TGF-β/smad2" signaling axis that drives LUAD metastasis, providing a potential novel target for prognosis assessment and targeted therapy in LUAD.