PHLDB2 (pleckstrin homology like domain family B member 2) is an oncogenic protein that promotes cancer progression through multiple mechanisms. The protein contains pleckstrin homology and SMC domains and functions as a key regulator of epithelial-mesenchymal transition (EMT) in various cancers 12. PHLDB2 is significantly upregulated in triple-negative breast cancer, head and neck squamous cell carcinoma, colorectal cancer, and gastric cancer, correlating with poor prognosis and enhanced metastasis 1234. Mechanistically, PHLDB2 promotes EMT by downregulating E-cadherin through interaction with MDM2, facilitating E-cadherin degradation 4. The protein also stabilizes EGFR and promotes its nuclear translocation, contributing to cetuximab resistance in colorectal cancer 3. Additionally, PHLDB2 forms dynamic condensates through liquid-liquid phase separation, which drives ECM remodeling and signal organization 1. PHLDB2 expression is regulated by tumor suppressor microRNAs miR-29c-3p and miR-491-5p/miR-875-5p, and activates downstream Akt-mTOR signaling 56. These findings establish PHLDB2 as a promising therapeutic target and prognostic biomarker across multiple cancer types.