Ribosomal Protein RPL7A Drives Lung Cancer Growth by Dismantling a Key Longevity Enzyme

Lung adenocarcinoma (LUAD) accounts for roughly 40% of all lung cancers and carries a dismal 5-year survival rate near 15%. Despite advances in targeted therapy and immunotherapy, the molecular drivers of LUAD progression remain incompletely understood. This study focuses on RPL7A, a large ribosomal subunit protein, and uncovers a previously unrecognized oncogenic mechanism operating independently of the classical RPL–MDM2–p53 tumor suppressor axis.

Using single-cell transcriptomic datasets and bioinformatics, the authors identified RPL7A as significantly upregulated in metastatic LUAD tissues compared with primary tumors and normal lung epithelium. Clinical validation across patient biopsy samples confirmed elevated RPL7A expression correlates with LUAD occurrence and poor overall survival (hazard ratio >1). In vitro knockdown of RPL7A in A549, H1299, and PC9 cell lines substantially reduced migration, invasion, and proliferation, while RPL7A overexpression had the opposite effect. Subcutaneous xenograft mouse models corroborated these findings in vivo.

The central mechanistic discovery is a molecular cascade linking RPL7A to altered lipid metabolism. RPL7A promotes the biogenesis of circRANBP17, a circular RNA previously implicated in LUAD metastasis and lipid reprogramming. RNA immunoprecipitation, fluorescence in situ hybridization, and pull-down assays demonstrated that circRANBP17 physically interacts with UPF1, an RNA helicase and nonsense-mediated decay factor. This circRANBP17–UPF1 complex binds to and destabilizes the mRNA of SIRT6—a NAD+-dependent deacylase that normally suppresses de novo lipogenesis by inhibiting key enzymes such as FASN and ACC. The resulting SIRT6 downregulation unleashes lipogenic programs and activates the AKT signaling pathway, both of which fuel tumor aggressiveness. Actinomycin D mRNA stability assays confirmed that SIRT6 mRNA half-life is significantly shortened in the presence of the circRANBP17–UPF1 complex.

These findings are notable for several reasons. First, they establish a non-canonical, extra-ribosomal function for RPL7A in cancer biology. Second, they connect ribosomal protein dysregulation to circular RNA-mediated post-transcriptional control of a sirtuin—a class of enzymes with well-established roles in aging, metabolism, and cancer suppression. SIRT6 in particular has been recognized as a longevity-associated protein that restrains glycolysis and lipogenesis; its degradation here provides a mechanistic link between ribosomal protein overexpression and metabolic reprogramming in LUAD.

The study positions RPL7A as a promising therapeutic target and suggests that disrupting the circRANBP17–UPF1 interaction or restoring SIRT6 expression could represent viable strategies for LUAD treatment. However, the work is primarily preclinical, and translation to clinical application will require further validation.