USP18-stabilized ELF3 drives glycolysis and malignant progression in lung adenocarcinoma.

E74-like ETS transcription factor 3 (ELF3) has been implicated in various tumorigenesis and inflammatory diseases. However, its expression profile and role in lung adenocarcinoma (LUAD) remain poorly defined. In the present study, through comprehensive clinical and experimental analyses, we aim to clarify the association between ELF3 overexpression in LUAD tissues and poor prognosis. Functional assays reveal that ELF3 knockdown inhibits the proliferation, migration, and invasion of LUAD cells, while ELF3 overexpression enhances these functions. Pathway enrichment analysis indicates that ELF3 influences the metabolic processes of LUAD. Mechanistically, ELF3 exerts oncogenic effects by regulating the transcription of hexokinase 2 (HK2) and glucose transporter type 1 (GLUT1). High-throughput screening reveals that dacinostat, by targeting the active site of the ELF3 protein, attenuates the glycolytic, proliferative, and metastatic abilities of LUAD cells. Additionally, ubiquitin-specific peptidase 18 (USP18) strengthens the stability of the ELF3 protein and influences the malignant biological behavior of LUAD through ELF3. In conclusion, the USP18/ELF3/HK2 and USP18/ELF3/GLUT1 axes play critical roles in glucose metabolism, proliferation, and metastasis of LUAD cells. Dacinostat inhibits the malignant progression of LUAD by targeting ELF3, providing strong evidence for developing novel therapeutic strategies targeting ELF3.