MTP18 as a prognostic biomarker and therapeutic target in lung adenocarcinoma

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.

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.

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.

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.