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A targetable FTO/SLC7A11/CBS/CTH axis controls cysteine metabolism, growth and survival in NSCLC

Nishanth Kuganesan1, Margaret Pan1, Haowen Jiang1

  • 1Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.

Science Advances
|July 3, 2026
PubMed

Insights

The RNA demethylase FTO targets cysteine metabolism in non-small cell lung cancer (NSCLC). Inhibiting FTO depletes glutathione, increases reactive oxygen species (ROS), and causes cancer cell death, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Cysteine metabolism is vital for non-small cell lung cancer (NSCLC) growth.
  • The precise regulatory mechanisms of cysteine metabolism in NSCLC remain unclear.

Purpose of the Study:

  • To investigate the role of the RNA demethylase FTO in regulating cysteine metabolism in NSCLC.
  • To evaluate FTO as a potential therapeutic target for NSCLC treatment.

Main Methods:

  • Genetic and pharmacologic inhibition of FTO in NSCLC cells and xenograft models.
  • Assays for cystine uptake, transsulfuration activity, glutathione levels, and reactive oxygen species (ROS).
  • Analysis of SLC7A11, cystathionine β-synthase (CBS), and cystathionine γ-lyase (CTH) expression.
  • Evaluation of tumor growth and combination therapy with radiotherapy.

Main Results:

  • FTO inhibition reduced cystine uptake and transsulfuration activity.
  • Decreased intracellular glutathione and elevated ROS levels were observed, leading to DNA damage and cell death.
  • FTO was found to promote the expression of SLC7A11, CBS, and CTH.
  • FTO inhibition reduced tumor growth and showed additive effects with radiotherapy in NSCLC xenografts.

Conclusions:

  • FTO plays a significant role in driving cysteine metabolism in NSCLC.
  • Targeting FTO and cysteine metabolism presents a promising therapeutic strategy for NSCLC.
  • This study highlights the potential of targeting cancer epitranscriptomics for NSCLC therapy.

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