METTL5 reprograms glycolytic metabolism and promotes non-small cell lung cancer progression by modifying PGAM1

N⁶-methyladenosine (m⁶A) RNA methylation is implicated in cancer metabolism; however, to the best of our knowledge, the role of methyltransferase 5 (METTL5) in non-small cell lung cancer (NSCLC) progression remains unclear. Reprogrammed glycolytic metabolism (Warburg effect) supports tumor growth and immune evasion; however, the regulatory mechanisms of this process require further investigation. We hypothesized that METTL5 drives NSCLC progression by regulating glycolytic metabolism through m⁶A modification of phosphoglycerate mutase 1 (PGAM1) mRNA. The present study aimed to elucidate the molecular mechanisms, functional impacts and clinical relevance of the METTL5/PGAM1 axis. Integrated analyses of NSCLC cohorts from The Cancer Genome Atlas database were performed, and in vitro models (A549 and PC9 cell lines) and molecular techniques, including methylation inhibition, RNA stability assays and metabolic flux measurements (Seahorse XFe96 analyzer), were used. Key interactions were validated through western blotting, reverse transcription-quantitative PCR and correlation analyses. METTL5 was significantly upregulated in NSCLC tissues and in A549, PC9 and H520 cell lines, and high METTL5 expression was associated with poor patient survival (P<0.05). Silencing of METTL5 suppressed NSCLC cell proliferation and migration, while overexpression promoted proliferation and migration. METTL5 directly targeted PGAM1 mRNA through m⁶A modification, and the expression levels of METTL5 and PGAM1 exhibited a statistically significant but moderate positive correlation (R=0.45; P=5.4×10^-56). YTH N⁶-methyladenosine RNA binding protein 1 (YTHDF1) is an m6A reader that recognizes and binds to methylated PGAM1 mRNA, enhancing its stability and expression. PGAM1 knockdown reduced glycolysis (decreased extracellular acidification rate) and increased oxidative phosphorylation (increased oxygen consumption rate). Notably, the positive correlation between PGAM1 and GLUT1 expression (R=0.6; P=4.12×10^-183) supports the role of the METTL5/PGAM1 axis in regulating GLUT1, thereby influencing glycolytic flux. Rescue experiments demonstrated that PGAM1 overexpression reversed GLUT1 downregulation in METTL5-knockdown cells. Overall, METTL5 may drive NSCLC progression by reprogramming glycolytic metabolism through m⁶A modification of PGAM1 mRNA. The METTL5/PGAM1/GLUT1 axis represents a novel therapeutic target for NSCLC.