Abstract
Lung adenocarcinoma (LUAD) remains the leading cause of cancer deaths worldwide. Apurinic/apyrimidinic endonuclease 1 (APE1), an enzyme integral to DNA repair and redox signaling, is notably upregulated in LUAD. Here we reveal that APE1 amplification, primarily via allele duplication, strongly correlates with poor prognosis in LUAD patients. Using human LUAD cell lines and a KRAS-driven mouse model, we showed that APE1 deletion hampered cell proliferation and tumor growth, highlighting its role in tumorigenesis. Mechanistically, APE1 promoted the transcription of urea cycle genes CPS1 and ARG2 by modulating the presence of G-quadruplex (G4) structures in their promoter regions. APE1 loss disrupted the urea cycle and pyrimidine metabolism, inducing metabolic reprogramming and growth arrest, which could be rescued by CPS1 or pyrimidine restoration. These findings uncover APE1's role in transcriptional regulation of urea cycle metabolic reprogramming via G4 structure, providing a potential therapeutic target LUAD patients with elevated APE1 expression.