Liquid‑liquid phase separation of PHLDB2 promotes oral squamous cell carcinoma metastasis through regulating epithelial mesenchymal transition and PIK3CA expression.
Liquid‑liquid phase separation (LLPS) contributes to multiple cellular bioprocesses; however, its clinicopathological relevance to oral squamous cell carcinoma (OSCC) remains largely unexplored. In the present study an integrative multi‑omics analysis investigating the prognostic value and molecular functions of LLPS‑related genes (LLPSRGs) in OSCC was conducted by leveraging transcriptomics and clinical data from 302 cases in The Cancer Genome Atlas database and LLPSRGs. A total of two prognostically distinct molecular subtypes were stratified by unsupervised clustering analysis, and a robust prognostic signature comprising seven key LLPSRGs was developed through LASSO regression and multivariate Cox analysis. Functional enrichment analysis highlighted the involvement of this signature in epithelial‑mesenchymal transition (EMT), with PHLDB2 emerging as a core regulator. Notably, the PHLDB2 protein underwent LLPS and formed droplet condensates both outside and in OSCC cells. Moreover, functional experiments revealed that PHLDB2 depletion attenuated the malignant biological behavior of OSCC cells, including cell proliferation, stemness, invasion and migration, and PHLDB2 promoted OSCC progression by regulating the PI3K‑Akt signaling pathway and PIK3CA expression. Retrospective clinical cohort and public dataset analyses validated that high expression of PHLDB2 was significantly associated with lymph node metastasis, higher pathological grade and reduced survival in patients with OSCC. Collectively, the present study established an LLPS‑based prognostic signature for OSCC, and revealed that phase separation of PHLDB2 may drive OSCC progression through regulating EMT and PIK3CA.