FTO Inhibition Depletes Cysteine Metabolism and Sensitizes NSCLC to Radiation Therapy

Metabolic rewiring is a major cause of therapeutic resistance in tumors. Targeting cysteine metabolism is an attractive strategy due to its crucial role in maintaining oxidative stress.

Here we demonstrate that FTO promotes NSCLC growth and survival by orchestrating cysteine metabolism through transcriptional regulation of the cystine transporter SLC7A11 and the de novo transsulfuration pathway enzymes cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH). Genetic and pharmacological inhibition of FTO reduced cystine uptake and de novo cysteine synthesis, leading to depleted intracellular glutathione (GSH), elevated reactive oxygen species (ROS), and reduced tumor growth.