DPEP2 (dipeptidase 2) is a membrane-associated enzyme with dual roles in dipeptidase catalysis and immune regulation. Beyond its enzymatic activity cleaving dipeptides, DPEP2 functions as a critical anti-inflammatory regulator that suppresses macrophage activation and NF-κB signaling 1. Mechanistically, DPEP2 inhibits inflammatory signal transduction by restraining MAP3K7, preventing NF-κB and p38 MAPK pathway activation 1. DPEP2 also regulates leukotriene D4 (LTD4) metabolism; its loss increases LTD4-mediated prostaglandin E2 overproduction, amplifying inflammatory responses 2. Additionally, DPEP2 controls macrophage infiltration through the Akt1-vimentin axis, where DPEP2 loss enhances macrophage migration and tissue invasion 3. Clinically, DPEP2 downregulation is associated with poor prognosis across multiple contexts. In lung adenocarcinoma, low DPEP2 correlates with enhanced epithelial-mesenchymal transition, cancer stemness, and cisplatin resistance 4. In p53-mutant NSCLC, DPEP2 suppresses tumor metastasis and M2 macrophage polarization via NF-κB inhibition 5. In sepsis, reduced DPEP2 expression in monocytes/macrophages correlates with inflammation severity and poor outcomes; LNP-mediated DPEP2 delivery mitigates hyperinflammation 2. DPEP2 emerges as both a prognostic biomarker and therapeutic target for inflammatory and malignant diseases 6.