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FTO Inhibition Depletes Cysteine Metabolism and Sensitizes NSCLC to Radiation Therapy

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307183 | GEO | 2026/04/06

REPOSITORIES: GEO

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Project description:In this study, we combined metabolic reconstruction, growth assays, metabolome and transcriptome analyses to obtain a global view of the sulfur metabolic network and of the response to sulfur availability in Brevibacterium aurantiacum. In agreement with the growth of B. aurantiacum in the presence of sulfate and cystine, the metabolic reconstruction showed the presence of a sulfate assimilation pathway and of thiolation pathways that produce cysteine (cysE and cysK) or homocysteine (metX and metY) from sulfide, of at least one gene of the transsulfuration pathway (aecD) and of genes encoding three MetE-type methionine synthases. We also compared the expression profiles of B. aurantiacum ATCC9175 during sulfur starvation and in the presence of sulfate, cystine or methionine plus cystine. In sulfur starvation, 690 genes including 21 genes involved in sulfur metabolism and 29 genes encoding amino acids and peptide transporters were differentially expressed. We also investigated changes in pools of sulfur-containing metabolites and in expression profiles after growth in the presence of sulfate, cystine or methionine plus cystine. The expression of genes involved in sulfate assimilation and cysteine synthesis was repressed in presence of cysteine, while the expression of metX, metY, metE1, metE2 and BL613 encoding a probable cystathionine-γ-synthase decreased in the presence of methionine. We identified three ABC transporters: two stronger transcribed during cysteine limitation and one during methionine depletion. Finally, the expression of genes encoding a methionine γ-lyase, BL929, and a methionine transporter (metPS) was induced in the presence of methionine, in conjunction with a significant increase of volatile sulfur compounds production. Refer to individual Series. This SuperSeries is composed of the following subset Series: GSE25418: BA-Methionine plus Cystine vs Cystine GSE25419: BA-Sulfate vs Cystine GSE25420: BA-Methionine plus Cystine vs Sulfate GSE25421: BA-Sulfate vs Sulfate starvation

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FTO Inhibition Depletes Cysteine Metabolism and Sensitizes NSCLC to Radiation Therapy

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