SUSD2 suppresses lung adenocarcinoma tumorigenesis by inducing autophagy <i>via</i> inhibiting PI3K/AKT/mTOR signaling pathway

Lung adenocarcinoma (LUAD) is the most common and aggressive non-small cell lung cancer with limited therapeutic options. SUSD2 exhibits varying regulatory behaviors in different types of tumors, its role in LUAD remains unclear. This study aims to determine the role of SUSD2 in LUAD and explore the underlying mechanism. Through TCGA database analysis, we discovered that SUSD2 expression is significantly downregulated in LUAD tissues, and its low expression is closely associated with advanced disease stages and poor patient prognosis. Further immunohistochemical validation confirmed reduced SUSD2 expression in clinical samples. Functional assays demonstrated that SUSD2 overexpression markedly inhibits LUAD cell proliferation, migration, and invasion, and also suppresses tumor growth and metastasis in mouse models. Mechanistic studies revealed that SUSD2 overexpression promotes autophagic flux (indicated by increased LC3-II and decreased p62) and suppresses the PI3K/AKT/mTOR signaling pathway. The antitumor effects of SUSD2 were attenuated by the autophagy inhibitor 3-MA or ATG5 knockdown, while reactivation of mTOR reversed SUSD2-induced autophagy and tumor suppression. In summary, SUSD2 functions as a tumor suppressor in LUAD by inducing autophagy and inhibiting the PI3K/AKT/mTOR pathway, suggesting its potential as a therapeutic target and prognostic biomarker.