e20711 Background: Methionine adenosyltransferase 2A (MAT2A) links metabolic reprogramming with epigenetic regulation by producing S-adenosylmethionine (SAM) in the methionine cycle. The regulatory mode of MAT2A in metabolic reprogramming of non-small cell lung cancer (NSCLC) is still unclear. The current efficacy of MAT2A inhibitors is limited, and further exploration is needed to improve their effectiveness. Methods: We systematically characterized the metabolic reprogramming of MAT2A rewiring in NSCLC cell lines treated with siRNA targeting MAT2A or inhibitor AG-270 using proteomics and metabolomics, supplemented by targeted metabolomics, RT qPCR, and ATAC seq, in order to characterize MAT2A-rewired metabolic reprogramming and identify potential combination strategies. Results: Knockout and inhibition of MAT2A significantly disrupt fatty acid biosynthesis, cholesterol metabolism, glycolysis, and transsulfuration pathway. In fatty acid biosynthesis, MAT2A affects the expression of key genes FASN and SCD, as well as the levels of key metabolites palmitic acid (PA) and oleic acid (OA), as exogenous PA reverses the cell growth inhibition caused by AG-270.In cholesterol metabolism, MAT2A regulates biosynthesis and efflux, binding AG-270 to liver X receptor agonists to promote cholesterol efflux and enhance anti-tumor efficacy. In energy metabolism, MAT2A affects glycolysis by regulating HIF1A. GLUT1 inhibitors that inhibit glucose uptake exhibit a synergistic effect when combined with AG-270. In the sulfur conversion pathway, MAT2A transcriptionally regulates the key enzyme CBS involved in cysteine biosynthesis. The combination therapy of AG-270 and inhibitors targeting genes upregulated by AG-270, such as PHGDH and SLC7A11, shows a synergistic effect. The former produces serine through cysteine biosynthesis, while the latter mediates cysteine uptake. Conclusions: Overall, our research findings confirm that MAT2A is a critical regulatory factor in NSCLC metabolism and propose a reasonable combination strategy to enhance the efficacy of MAT2A inhibitors.
Fang et al. (Thu,) studied this question.