Yichen Zhu, Jing Han, Yan Pan, Yan Liu, Yan Liu, Zhe Zhang, Haiyang Chen, Si Zhou, Zhenqiang Sun, Yang Liu, Yang Liu, Qiming Wang
BACKGROUND: Lung cancer, primarily lung adenocarcinoma (LUAD), is the leading cause of cancer-related deaths worldwide. Despite extensive research, the mechanisms behind LUAD progression remain inadequately understood, underscoring the need for new biomarkers and therapeutic targets. Ribosomal proteins, traditionally associated with protein synthesis, are gaining recognition for their roles in tumorigenesis, though many functions remain unexplored. METHODS: This study utilized single-cell transcriptomic data and bioinformatics analyses to identify potential LUAD biomarkers. Selected biomarkers were validated using quantitative PCR (qPCR) and immunofluorescence on clinical samples. Functional roles were assessed through in vivo and in vitro assays, including migration, invasion, and proliferation studies. Mechanistic insights were gained via mRNA stability assays, RNA immunoprecipitation, fluorescence in situ hybridization, and dual luciferase reporter assays. RESULTS: RPL7A is a significant prognostic marker with elevated expression in metastatic LUAD tissues. Clinical validation shows that high RPL7A expression correlates with LUAD occurrence and poor overall survival (OS) (hazard ratio > 1). RPL7A knockdown inhibits LUAD cell migration, invasion, and proliferation, underscoring its key role in tumor progression. Mechanistically, RPL7A impacts lipid metabolism and the AKT pathway. Crucially, RPL7A regulates circRANBP17, a circRNA linked to LUAD metastasis and lipid metabolism. This interaction forms a complex with UPF1 to destabilize SIRT6 mRNA, a critical factor in lipogenesis. The resulting downregulation of SIRT6 highlights how RPL7A and circRANBP17 contribute to altered lipid metabolism and tumor progression in LUAD. CONCLUSIONS: Our findings demonstrate that RPL7A promotes LUAD progression through circRANBP17-UPF1-mediated SIRT6 degradation, positioning RPL7A as a potential therapeutic target in LUAD.