Integrating proteomics and metabolomics to reveal MAT2A for metabolic reprogramming and relative combination strategies in non-small cell lung cancer

In lipid metabolism, MAT2A inhibition impaired cell proliferation by suppressing fatty acid biosynthesis, and induced cholesterol biosynthesis and efflux impairment. Combining MAT2A inhibitors with the liver X receptor agonist LXR-623, which facilitated cholesterol efflux, effectively depleted intracellular cholesterol and augmented anti-tumor efficacy. In energy metabolism, MAT2A mainly inhibited glycolysis through HIF1A regulation and GLUT1 inhibitor BAY-876 demonstrated a synergetic effect when combined with AG270.

In the transsulfuration pathway, MAT2A transcriptionally regulated a key enzyme CBS, and combination treatments using AG270 with either the SLC7A11 inhibitor HG106 or the PHGDH inhibitor NCT-503 exhibited enhanced anti-tumor activity. Overall, our findings identified MAT2A as a critical regulator of metabolic networks in NSCLC and propose several rational combination therapies to enhance MAT2A inhibitor efficacy.