Integrating proteomics and metabolomics to reveal MAT2A for metabolic reprogramming in non-small cell lung cancer cells.

Methionine adenosyltransferase 2A (MAT2A) links metabolic reprogramming to epigenetic regulation via S-adenosylmethionine (SAM) production, but its role in non-small cell lung cancer (NSCLC) remains unclear, and current inhibitors require combination strategies. Using proteomics and metabolomics in NSCLC cells treated with MAT2A-targeting siRNA or the inhibitor AG-270, we characterized MAT2A-driven metabolic rewiring. In fatty acid biosynthesis, MAT2A regulates FASN and SCD; exogenous palmitic acid reverses AG-270-induced growth inhibition, supporting combination with the FASN inhibitor TVB-2640. In cholesterol metabolism, MAT2A modulates biosynthesis and efflux, and an LXR agonist promoting cholesterol efflux enhances AG-270 efficacy. In energy metabolism, MAT2A governs glycolysis via HIF1A, and a GLUT1 inhibitor synergizes with AG-270. In the transsulfuration pathway, MAT2A transcriptionally regulates CBS and shows synergy with inhibitors of PHGDH (producing serine for cysteine biosynthesis) and SLC7A11 (mediating cysteine uptake). Collectively, our findings establish MAT2A as a central metabolic regulator in NSCLC and propose rational combination strategies.