Hippo Pathway Drives Durable Non‐Cell‐Autonomous Ferroptosis Resistance in Lung Cancer

The Hippo pathway effector Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) play a critical role in promoting lung cancer progression, but paradoxically increase tumor cell sensitivity to ferroptosis, a form of lipid peroxidation-driven cell death. The mechanism through which YAP/TAZ-high cells evade ferroptosis during cancer progression remains unclear. Here, we showed that YAP/TAZ-low lung cancer cells confer durable ferroptosis resistance to neighboring YAP/TAZ-high cells through a non-cell-autonomous mechanism. Using murine lung carcinoma cell coculture models, we demonstrated that transient exposure to YAP/TAZ-deficient cells induces a stable, contact-independent ferroptosis-resistant state in wild-type (WT) cells, enhancing their metastatic seeding capacity in vivo. This adaptation is mediated by the upregulation of Gch1, which encodes GTP cyclohydrolase 1 and suppresses ferroptosis via the synthesis of the antioxidant metabolite tetrahydrobiopterin (BH4). GCH1 overexpression alone was sufficient to confer ferroptosis resistance in WT cells, whereas conditioned medium from YAP/TAZ-deficient cells replicated this effect, indicating that a soluble factor is involved in Gch1 induction. Importantly, the genetic deletion of Gch1 in YAP/TAZ-deficient cells abolished their ability to protect WT cells, confirming its essential role in this intercellular program. Our findings revealed a Hippo pathway-linked ferroptosis resistance mechanism and suggested that intra-tumoral heterogeneity in YAP/TAZ activity promotes metastatic fitness by enabling the survival of ferroptosis-prone cells via antioxidant signaling.