FTO Inhibition Depletes Cysteine Metabolism and Sensitizes NSCLC to Radiation Therapy

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality, underscoring the urgent need for novel therapeutic strategies. 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. We further show that FTO inhibition increases radiation-induced DNA damage and sensitizes NSCLC cells and xenograft tumors to radiation therapy (RT). These findings establish FTO as a pivotal epitranscriptomic regulator of cysteine metabolism and radiation response in NSCLC, revealing a novel metabolic vulnerability that can be exploited therapeutically. Targeting FTO presents a promising strategy to enhance the efficacy of RT and improve outcomes for patients with NSCLC.