RPL35A drives aerobic glycolysis and tumorigenesis by facilitating MYC-mediated SKP2 transcription

As a ribosomal protein, RPL35A participates in diverse cellular processes, yet its role in lung cancer remains unclear. Here, we demonstrate that RPL35A is upregulated in lung cancer tissues and correlates with poor patient prognosis. Functional studies show that RPL35A overexpression enhances proliferation, migration, and invasion of lung cancer cells while suppressing apoptosis; conversely, RPL35A knockdown produces opposing effects. In vivo xenograft models confirm that RPL35A depletion significantly inhibits tumor growth. Mechanistically, RPL35A directly interacts with the oncoprotein MYC through its N-terminal domain (amino acids 2-22), facilitating MYC nuclear translocation and recruitment to the SKP2 promoter. This interaction drives SKP2 expression, leading to activation of aerobic glycolysis, as evidenced by increased glucose uptake, lactate production, and extracellular acidification rate. Deletion of the 2-22 residue motif (RPL35A-Δ1) abolishes MYC binding and fails to restore SKP2 expression or glycolytic activity in rescue experiments. Furthermore, the oncogenic effects of RPL35A are abrogated by glycolysis inhibition, confirming metabolic reprogramming as a key downstream effector. Collectively, our findings suggest that RPL35A may serve as a valuable prognostic biomarker for lung squamous cell carcinoma (LUSC) patients and a promising therapeutic target.