Decoding YAP's role in oral cancer metastasis: A systematic synthesis of experimental and clinical evidence

Background: Yes-associated protein (YAP), the key effector of Hippo signaling, is implicated in oncogenesis and metastasis in oral squamous cell carcinoma (OSCC). Prior reports vary in assay, model, and outcome definitions, limiting clear clinical translation. Methods: Following PRISMA 2020, we searched PubMed, Scopus, and Web of Science to February 2025 for original studies evaluating YAP in OSCC across clinical, in vitro, and in vivo models. Data items included assay type, subcellular localization, phenotypic outcomes, and comparators. Risk of bias was assessed using the ROBINS-I tool. Given the heterogeneity, we used Synthesis Without Meta-analysis with direction-of-effect tabulation across prespecified domains: epithelial-to-mesenchymal transition, migration or invasion, in vivo tumor growth, and clinical survival. We also prespecified effect-modifier reporting for HPV or p16 status, immune contexture, and treatment modality. Results: Thirteen studies met criteria. Healthy oral mucosa comparators were absent; one study included dysplasia. Demographic variables were inconsistently reported and were not pooled. Most studies used immunohistochemistry or western blot, with frequent emphasis on nuclear YAP localization as a proxy for activity. ROBINS-I judgments were mainly moderate risk, with one serious judgment; excluding the latter did not change conclusions. Direction-of-effect synthesis showed high consistency: pro-oncogenic direction in 12 of 13 studies overall; by domain, unfavorable direction in all studies assessing epithelial-to-mesenchymal transition, migration or invasion, and in vivo tumor growth, and in three of four studies assessing survival, with one favorable survival signal in a ferroptosis-linked context. Early clinical translation of TEAD inhibitors (IK-930 and VT3989) is underway in tumor-agnostic trials, although OSCC-specific efficacy data are not yet available. Conclusions: Evidence across models supports YAP as a strong candidate driver of aggressive OSCC biology and a promising therapeutic target whose independent prognostic and predictive roles require prospective validation. Standardised evaluation is needed, including antibody metadata and validation, quantitative nuclear scoring and nuclear-to-cytoplasmic ratios, phospho-YAP, and a small TEAD target-gene panel. Future OSCC studies should stratify by HPV or p16 status, immune contexture, and treatment to clarify prognostic independence and to guide biomarker-selected trials of TEAD inhibition.