DUSP3 (dual specificity phosphatase 3), also known as VHR (vaccinia H1-related phosphatase), is a protein tyrosine phosphatase that preferentially dephosphorylates phosphotyrosine residues 12. Its primary substrates include ERK1 and ERK2, which it inactivates to negatively regulate MAPK signaling cascades 12. DUSP3 operates through both MAPK-dependent and MAPK-independent mechanisms to regulate diverse cellular processes including cell-cycle regulation, DNA damage response, platelet activation, and angiogenesis 34. In cancer biology, DUSP3 exhibits context-dependent roles as either a tumor suppressor or tumor-promoting enzyme across different malignancies 56. In osteosarcoma, DUSP3 overexpression inhibits cell proliferation, migration, invasion, and stemness through modulation of the EGFR/STAT3/SOX2 axis 7. Beyond oncology, DUSP3 regulates immune responses; knockdown enhances NF-κB signaling and cytokine production during bacterial infection 8. DUSP3 expression serves as a biomarker for tuberculosis infection diagnosis 9 and may be therapeutically relevant for renal ischemia/reperfusion injury 10. The broad substrate diversity and MAPK-independent functions position DUSP3 as a druggable target for multiple human diseases 5.