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

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.