DUSP28 (dual specificity phosphatase 28) is an atypical member of the dual-specificity phosphatase family with intrinsically low phosphatase activity. Biochemically, DUSP28 displays phosphatase activity toward synthetic substrates but exhibits minimal activity against phosphotyrosine and phosphothreonine, with complete lack of activity against phosphoserine 1. This poor substrate accessibility results from bulky nonconserved amino acid residues in the catalytic pocket that obstruct substrate entry 1. Despite limited enzymatic activity, DUSP28 functions as a potent oncogenic driver across multiple cancer types. In hepatocellular carcinoma, DUSP28 overexpression promotes cell proliferation and cell cycle progression via p38 MAPK pathway activation 2. In pancreatic cancer, DUSP28 mediates chemoresistance and migration through multiple mechanisms: ERK1/2 pathway activation 3, PDGF-A autocrine signaling 4, and mucin (MUC5B/MUC16) regulation 5. Secreted DUSP28 additionally functions in autocrine and paracrine signaling via integrin α1 interaction, promoting tumor growth and angiogenesis 6. In breast cancer, DUSP28 activates the Akt/β-catenin/Slug axis to promote proliferation and invasion 7. Clinically, DUSP28 represents a prognostic biomarker and therapeutic target in multiple malignancies, with circulating DUSP28 potentially useful for cancer patient monitoring 6.