YAP induces ferroptosis vulnerability in breast cancer via GCH1 suppression.

Ferroptosis, an iron-dependent form of regulated cell death, has emerged as a therapeutic vulnerability in various cancers. Recent studies have revealed functional links between YAP (Yes-associated protein) and ferroptosis sensitivity in several malignancies; however, this relationship remains uncharacterized in breast cancer. Here, we investigated the role of YAP in regulating ferroptosis sensitivity in breast cancer. Analysis of patient cohorts revealed that YAP activity correlates with advanced disease and ferroptosis-associated gene signatures. Consistently, among murine breast cancer cell lines with distinct metastatic potential, metastatic 4T1 cells exhibited higher YAP activity and greater ferroptosis sensitivity than non-metastatic 67NR cells. Overexpression of a constitutively active YAP mutant was sufficient to enhance ferroptosis sensitivity in 67NR cells. Mechanistically, YAP repressed expression of GCH1 (GTP cyclohydrolase 1), the rate-limiting enzyme in the synthesis of the antioxidant metabolite tetrahydrobiopterin (BH4). Restoration of GCH1 expression or BH4 supplementation reduced ferroptosis sensitivity in YAP-overexpressing cells. Collectively, our findings demonstrate that oncogenic YAP signaling confers a ferroptosis-associated vulnerability through suppression of the GCH1-BH4 antioxidant pathway, providing a rationale for ferroptosis-based therapeutic strategies in YAP-driven breast cancer.