Lactylation-Mediated METTL14 Promotes Glycolysis Through Facilitating PGAM1 m6A Methylation in Non-Small Cell Lung Cancer.

[OBJECTIVE] Non-small cell lung cancer (NSCLC) accounts for the highest proportion of lung cancers. METTL14 is a m6A methyltransferase affects the development of NSCLC. Lactylation can induced by glycolysis production lactate, but whether it modulates NSCLC through m6A methylation remains unclear. We aimed to determine whether METTL14 mediates NSCLC through glycolysis.

[METHODS] METTL14 expression was validated in NSCLC clinical samples. Effects of METTL14 knockdown in NSCLC cells were evaluated by cell viability, colony formation and glycolysis. Lactylation was detceted by IP and western blotting.

[RESULTS] We observed elevated METTL14 in NSCLC tissues and cells. METTL14 knockdown reduced cell viability, cell proliferation and glycolysis in NSCLC cells and tumor development . PGAM1 was the downstream target of METTL14, and METTL14 knockdown inhibited m6A level and mRNA stability of PGAM1. PGAM1 overexpression reversed the effect on METTL14 knockdown in NSCLC cells. Moreover, pan-lactylation, METTL14 expression and lactylation were upregulated in NSCLC tumor tissues, and exogenous promotion or inhibition of overall lactylation can promote or inhibit the lactylation level and protein stability of METTL14, respectively.

[CONCLUSION] Lactylation enhanced METTL14 expression, thereby promoting PGAM1 m6A methylation to facilitate glycolysis in NSCLC. This finding uncovers a novel metabolic regulatory axis and offers a potential therapeutic target for NSCLC intervention.