2. Academic Validation
  3. Hippo pathway controls biopterin metabolism to shield adjacent cells from ferroptosis in lung cancer

Hippo pathway controls biopterin metabolism to shield adjacent cells from ferroptosis in lung cancer

  • EMBO Rep. 2025 Aug;26(16):4124-4152. doi: 10.1038/s44319-025-00515-4.
Hao Li 1 2,  Yohei Kanamori # 1,  Akihiro Nita # 3,  Ayato Maeda 1 3,  Tianli Zhang 4 5,  Kenta Kikuchi 6,  Hiroyuki Yamada 7 8,  Touya Toyomoto 4,  Mohamed Fathi Saleh 1 3,  Mayumi Niimura 1,  Hironori Hinokuma 1 8,  Mayuko Shimoda 1,  Koei Ikeda 8,  Makoto Suzuki 8,  Yoshihiro Komohara 7 9,  Daisuke Kurotaki 6 9,  Tomohiro Sawa 4,  Toshiro Moroishi 10 11 12
Affiliations

Affiliations

  • 1 Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
  • 2 Department of Biomedical Sciences, School of Biological and Environmental Sciences, Kwansei Gakuin University, 1 Gakuen Uegahara, Sanda, 669-1330, Japan.
  • 3 Division of Cellular Dynamics, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo, 1-5-45 Yushima, Tokyo, 113-8510, Japan.
  • 4 Department of Microbiology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
  • 5 Center for Integrated Control, Epidemiology and Molecular Pathophysiology of Infectious Diseases, Akita University, 1-1-1 Hondo, Akita, 010-8543, Japan.
  • 6 Laboratory of Chromatin Organization in Immune Cell Development, International Research Center for Medical Sciences, Kumamoto University, 2-2-1 Honjo, Kumamoto, 860-0811, Japan.
  • 7 Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
  • 8 Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
  • 9 Center for Metabolic Regulation of Healthy Aging, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan.
  • 10 Department of Molecular and Medical Pharmacology, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. moroishi.toshiro@tmd.ac.jp.
  • 11 Division of Cellular Dynamics, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo, 1-5-45 Yushima, Tokyo, 113-8510, Japan. moroishi.toshiro@tmd.ac.jp.
  • 12 Center for Metabolic Regulation of Healthy Aging, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Kumamoto, 860-8556, Japan. moroishi.toshiro@tmd.ac.jp.
  • # Contributed equally.
PMID: 40619484 DOI: 10.1038/s44319-025-00515-4
Abstract

Recent advances in single-cell technologies have uncovered significant cellular diversity in tumors, influencing Cancer progression and treatment outcomes. The Hippo pathway controls cell proliferation through its downstream effectors: yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). Our analysis of human lung adenocarcinoma and murine models revealed that Cancer cells display heterogeneous YAP/TAZ activation levels within tumors. Murine lung Cancer cells with high YAP/TAZ activity grow rapidly but are sensitive to Ferroptosis, a cell death induced by lipid peroxidation. In contrast, cells with low YAP/TAZ activity grow slowly but resist Ferroptosis. Moreover, they protect neighbouring cells from Ferroptosis, creating a protective microenvironment that enhances the tumor's resistance to Ferroptosis. Mechanistically, inhibiting YAP/TAZ upregulates GTP cyclohydrolase 1 (GCH1), an enzyme critical for the biosynthesis of tetrahydrobiopterin (BH4), which functions as a secretory antioxidant to prevent lipid peroxidation. Pharmacological inhibition of GCH1 sensitizes lung Cancer cells to Ferroptosis inducers, suggesting a potential therapeutic approach. Our data highlights the non-cell-autonomous roles of the Hippo pathway in creating a ferroptosis-resistant tumor microenvironment.

Keywords

Biopterin; Cell Communication; Ferroptosis; Hippo Pathway; Lung Cancer.

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