YAP/TAZ Drive Oral Leukoplakia Progression and Confer Ferroptosis Vulnerability

Area of Science:

• Oncology
• Molecular Biology
• Oral Pathology

Background:

• Oral leukoplakia (OLK) is a common potentially malignant disorder with high recurrence and transformation rates.
• Current treatments for OLK are largely ineffective in preventing malignant transformation due to poorly understood underlying mechanisms.

Purpose of the Study:

• To identify specific cell populations and molecular pathways involved in OLK development and progression.
• To explore novel therapeutic strategies targeting OLK malignancy and preventing oral cancer.

Main Methods:

• Single-cell RNA sequencing was used to profile OLK tissues and identify distinct cell populations.
• Transgenic mouse models were employed to validate the role of identified pathways in OLK progression.
• Drug screening and combination therapy studies were conducted to assess therapeutic efficacy.

Main Results:

• A specific OLK cell population with overactivated YAP/TAZ pathways, disrupting epithelial homeostasis, was identified.
• YAP/TAZ activation was confirmed to drive the malignant phenotype and progression of OLK in mouse models.
• A ferroptosis vulnerability mediated by the YAP/TAZ-TEAD-TXNRD1 axis was uncovered in OLK malignant cells.
• Combination therapy with sulfasalazine and docosahexaenoic acid effectively induced ferroptosis and reduced OLK progression.

Conclusions:

• YAP/TAZ activation plays a dual role in OLK, maintaining malignancy while conferring ferroptosis vulnerability.
• Targeting ferroptosis presents a promising strategy for indirectly inhibiting YAP/TAZ and managing OLK.
• Repurposing existing drugs offers a practical approach to improve OLK treatment and reduce oral cancer risk.