BACE2 facilitates lung adenocarcinoma progression by enhancing mTORC1 signalling

Background Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer, with a poor prognosis due to radiotherapy and chemotherapy resistance. Novel systemic treatments have limitations, highlighting the need for identifying new oncogenic genes and therapeutic targets. Beta-secretase 2 (BACE2) is involved in the progression of multiple cancers, but its role and mechanism in LUAD remain unreported. This study aimed to explore the expression pattern, biological function, and underlying mechanism of BACE2 in LUAD. Methods BACE2 expression was assessed in LUAD tissues via bioinformatics analysis and immunohistochemistry. Cell viability, proliferation, apoptosis, migration, and cell cycle were detected using Cell Counting Kit-8 (CCK-8), 5-ethynyl-2’-deoxyuridine (EdU), flow cytometry, Transwell, and scratch assays. Gene set enrichment analysis (GSEA) and Western blot were used to explore the downstream pathway regulated by BACE2. A xenograft model was established to verify BACE2’s in vivo role. Results BACE2 expression was elevated in LUAD tissues and cell lines, and high BACE2 expression correlated with poor patient survival. Silencing BACE2 led to increased apoptosis, reduced cell viability, growth, and migration, and G2 phase arrest. GSEA identified the mammalian target of rapamycin complex 1 (mTORC1) signalling pathway as a downstream target of BACE2, which was confirmed by Western blot (reduced p-mTOR/mTOR and p-RPS6KB1/RPS6KB1 levels after BACE2 silencing). Inhibiting mTORC1 with rapamycin abrogated the oncogenic effects of BACE2 overexpression. In vivo, BACE2 knockdown significantly suppressed xenograft tumor growth. Conclusions BACE2 contributes to LUAD progression by activating the mTORC1 signalling pathway, providing a novel therapeutic target for LUAD treatment.