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YAP induces ferroptosis vulnerability in breast cancer via GCH1 suppression

Paweenapon Chunthaboon1, Mohamed Fathi Saleh1, Yasuhisa Sakamoto2

  • 1Division of Cellular Dynamics, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo, Tokyo, Japan; Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Biochemical and Biophysical Research Communications
|May 19, 2026
PubMed

Insights

Oncogenic YAP signaling in breast cancer increases sensitivity to ferroptosis, a cell death process. This occurs by YAP suppressing GCH1, which reduces the antioxidant BH4, creating a therapeutic vulnerability.

Area of Science:

  • Oncology
  • Cell Death Research
  • Cancer Therapeutics

Background:

  • Ferroptosis is an iron-dependent cell death pathway implicated as a therapeutic vulnerability in cancer.
  • The role of Yes-associated protein (YAP) in ferroptosis sensitivity is known in some cancers but uncharacterized in breast cancer.

Purpose of the Study:

  • To investigate the role of YAP in regulating ferroptosis sensitivity in breast cancer.
  • To elucidate the molecular mechanisms by which YAP influences ferroptosis in breast cancer.

Main Methods:

  • Analysis of patient cohorts and murine breast cancer cell lines (4T1 and 67NR).
  • Overexpression of a constitutively active YAP mutant.
  • Assessment of GTP cyclohydrolase 1 (GCH1) expression and tetrahydrobiopterin (BH4) levels.
  • Manipulation of GCH1 expression and BH4 supplementation.

Main Results:

  • YAP activity correlated with advanced breast cancer and ferroptosis-associated gene signatures.
  • Metastatic 4T1 cells showed higher YAP activity and ferroptosis sensitivity than non-metastatic 67NR cells.
  • YAP overexpression enhanced ferroptosis sensitivity, mechanistically by repressing GCH1 expression and subsequently reducing BH4 levels.
  • Restoring GCH1 or supplementing BH4 mitigated YAP-induced ferroptosis sensitivity.

Conclusions:

  • Oncogenic YAP signaling confers a ferroptosis vulnerability in breast cancer.
  • This vulnerability is mediated by the suppression of the GCH1-BH4 antioxidant pathway.
  • Targeting YAP or the GCH1-BH4 pathway may offer novel therapeutic strategies for YAP-driven breast cancer.
Keywords:
BH4Breast cancerFerroptosisGCH1Hippo pathwayYAP

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