TESMIN promotes lung adenocarcinoma proliferation, migration and invasion via PI3K/AKT/mTOR signaling.

Lung adenocarcinoma (LUAD) lacks robust biomarkers that both forecast outcome and reveal actionable biology. The role of TESMIN (MTL5) in LUAD remains insufficiently defined. We combined TCGA-LUAD analyses with protein-level validation in clinical tissues, and performed gain- and loss-of-function studies in LUAD cell lines (TESMIN overexpression in H1299; knockdown in H292). Cellular phenotypes were assessed by CCK-8, EdU, wound healing, and Transwell assays, with cytoskeletal remodeling visualized by phalloidin staining. RNA-seq with GO/KEGG enrichment profiled TESMIN-related programs. Mechanistically, we quantified phosphorylation across the PI3K/AKT/mTOR axis and tested pathway dependence using the PI3K inhibitor GDC0941 and AKT inhibitor MK2206. Xenografts evaluated in vivo effects. TESMIN was upregulated in LUAD and associated with poorer overall survival. Functionally, TESMIN enhanced proliferation, migration, invasion, and actin remodeling in vitro, while its knockdown produced the opposite effects. Mechanistically, TESMIN increased phosphorylation of PI3K, AKT, and mTOR without altering total protein levels. Pharmacologic blockade with GDC0941 (PI3K) or MK2206 (AKT) reduced pathway phosphorylation (GDC0941: p-PI3K/p-AKT/p-mTOR; MK2206: p-AKT/p-mTOR) and reversed TESMIN-driven proliferation, motility, invasiveness, and cytoskeletal reorganization. In vivo, TESMIN overexpression accelerated xenograft growth, whereas TESMIN silencing restrained it. TESMIN promotes LUAD progression by functionally activating the PI3K/AKT/mTOR pathway. These multi-level data nominate TESMIN as a prognostic biomarker and a biologically grounded candidate target for LUAD.