Blocking methionine catabolism induces senescence and confers vulnerability to GSK3 inhibition in liver cancer

The availability of the essential amino acid methionine plays a crucial role in cellular metabolism and growth, with dietary methionine restriction proposed as a potential cancer therapy. However, the response of liver cancer cells to methionine deprivation and the underlying mechanisms remain poorly understood. In this study, we found that human liver cancer cells experience irreversible cell cycle arrest when deprived of methionine in vitro. Inhibition of methionine adenosyl transferase 2A (MAT2A), which is responsible for methionine catabolism, also induces cell cycle arrest and DNA damage, leading to cellular senescence.

Additionally, a pharmacological screening identified GSK3 inhibitors as senolytics that selectively eliminate MAT2A-inhibited senescent liver cancer cells. Notably, the combination of MAT2A and GSK3 inhibitors effectively reduces liver tumor growth in vitro and in vivo across various models. Overall, these findings suggest that methionine catabolism is critical for liver tumor growth, and its inhibition may serve as an effective pro-senescence strategy when combined with senolytic PF-9366 agents to treat liver cancer.