MTP18 as a prognostic biomarker and therapeutic target in lung adenocarcinoma.

BACKGROUND: Increasing evidence indicates that tumor cells alter mitochondrial morphology, regulated through fusion, fission, and mitophagy, to meet the demands of rapid proliferation and enhance survival. As a key regulator of mitochondrial dynamics, the biological role and mechanism of MTP18 in lung adenocarcinoma (LUAD) remain unclear. METHODS: MTP18 expression and prognostic value were analyzed using TCGA datasets and validated in clinical cohorts via qRT-PCR and IHC. Functional assays (CCK-8, Transwell, flow cytometry) were performed in MTP18-overexpressing or silenced A549 and PC9 cells. The regulatory mechanism involving mitochondrial dynamics, reactive oxygen species (ROS), and the PI3K/AKT pathway was elucidated using specific pharmacological modulators (Mdivi-1, MYLS22, NAC, H2O2, LY294002, 740Y-P) and transmission electron microscopy. RESULTS: MTP18 was significantly upregulated in LUAD and correlated with poor patient survival. Functionally, MTP18 overexpression promoted cell proliferation, metastasis, and S-phase entry, while inhibiting apoptosis. Mechanistically, MTP18 induced excessive mitochondrial fission, leading to a robust accumulation of intracellular ROS. This elevated oxidative stress acted as a second messenger to trigger the phosphorylation of PI3K and AKT. Blocking fission or scavenging ROS effectively abrogated MTP18-mediated pathway activation and malignant phenotypes. Additionally, preliminary analysis suggested an association between MTP18 and an immunosuppressive microenvironment. CONCLUSIONS: MTP18 functions as a novel oncogenic driver in LUAD by orchestrating a "fission-ROS-PI3K/AKT" signaling axis. Targeting MTP18-mediated mitochondrial dynamics offers a promising therapeutic strategy to disrupt both tumor growth and metabolic adaptation in LUAD.