YAP/TAZ Drive Oral Leukoplakia Progression and Confer Ferroptosis Vulnerability

Oral leukoplakia (OLK), the most common potentially malignant oral disorder, poses a persistent clinical challenge due to high recurrence and malignant transformation rates, with no curative treatment currently available. Conventional interventions, including medications, surgery, laser, and photodynamic therapy, have shown limited success in cancerization prevention, largely because the abnormal events underlying the development and progression of OLK remain poorly defined. Here, through single-cell RNA sequencing profiles, we identified an OLK-specific cell population characterized by YAP/TAZ overactivation, which was strongly associated with disrupted epithelial homeostasis. Transgenic mouse models confirmed the essential role of YAP/TAZ activation in conferring the malignant phenotype of OLK and driving its progression toward transformation. Interestingly, although YAP/TAZ are technically and strategically considered undruggable, we uncovered a ferroptosis vulnerability in OLK malignant cells mediated by the YAP/TAZ-TEAD-TXNRD1 axis. Notably, we demonstrate that combining sulfasalazine and docosahexaenoic acid, 2 clinically available agents, effectively induces ferroptosis and attenuates OLK progression. These findings establish a mechanistic link between YAP/TAZ activation and OLK progression, specifically revealing the dual roles of YAP/TAZ in maintaining malignant properties while conferring ferroptosis vulnerability. This duality highlights ferroptosis induction as a promising therapeutic strategy for indirectly targeting YAP/TAZ. Moreover, the drug-repurposing approach provides a practical and translationally relevant avenue to improve OLK management and reduce the risk of malignant transformation.