Crosstalk of the Hippo/YAP pathway in the progression of oral potentially malignant disorders to oral squamous cell carcinoma: a systematic review

Objective The aim of this review is to synthesize current evidence on the interaction between Hippo-YAP signaling and EMT in the malignant transformation of oral potentially malignant disorders (OPMDs) to oral squamous cell carcinoma (OSCC) and to examine their potential utility as biomarkers and therapeutic targets. Design: Following PRISMA 2020 guidelines, five electronic databases (PubMed, Web of Science, Scopus, LIVIVO, and Embase) were utilized for this search. Eligible studies included human tissue-based investigations and complementary in vitro experiments evaluating YAP/TAZ or EMT markers in OPMDs and OSCC. Risk of bias was assessed using QUIN, SYRCLE, and JBI tools. Results From 2,208 records, 12 studies (26 datasets) were included. Across study designs, Hippo-YAP dysregulation and EMT activation were consistently observed across the normal to OPMD to OSCC progression. YAP nuclear localization correlated with reduced E-cadherin and increased vimentin, N-cadherin, Snail, and Slug expression. Crosstalk between YAP and MAPK/ERK, PI3K/Akt/mTOR, and Wnt/β-catenin pathways further amplified EMT signaling. High YAP , hTERT , circEPSTI1 , and SNAI2 expression, together with low KLK6 , were associated with poor prognosis and increased malignant transformation risk. Pharmacologic inhibition of PI3 K/mTOR, MEK/ERK, or LSD1 reversed EMT phenotypes in experimental models. Conclusion: Integrated activation of Hippo-YAP and EMT pathways is a pivotal event in OPMD-OSCC progression. YAP -centered EMT regulation shows promise as both a biomarker of malignant potential and a therapeutic target for chemoprevention and early intervention.