OSBPL3 promotes LUAD metastasis and glycolysis through transcriptional upregulation of PLAU via NFE2L2.

The progression of lung adenocarcinoma (LUAD) involves multiple molecular determinants, among which Oxysterol-binding protein-like 3 (OSBPL3) has been suggested to contribute to tumorigenesis, though its functional significance in LUAD remains poorly characterized. In this study, we elucidate the oncogenic functions and underlying mechanisms of OSBPL3 in LUAD pathogenesis. Analysis of clinical specimens revealed upregulated OSBPL3 expression in LUAD, which correlated with unfavorable patient outcomes. Genetic depletion of OSBPL3 in vitro impeded cellular proliferation, migratory capacity, and cell cycle progression, while inducing apoptotic cell death. Mechanistically, OSBPL3 was found to interact with the transcription factor NFE2L2, promoting its nuclear translocation and enhancing the transcriptional activation of PLAU, a downstream target gene. Upregulation of PLAU subsequently stimulated expression of key glycolytic enzymes through PI3K/AKT pathway activation, resulting in increased glucose consumption and lactate secretion. This metabolic reprogramming toward aerobic glycolysis facilitated malignant progression. Both genetic inhibition of PLAU and pharmacological blockade of AKT signaling abrogated the tumor-promoting phenotypes induced by OSBPL3. In vivo, OSBPL3 silencing significantly attenuated tumor growth and promoted apoptosis. Collectively, these findings identify an OSBPL3-NFE2L2-PLAU-AKT signaling axis that drives glycolytic metabolism and LUAD progression, showing its potential as a therapeutic target.