{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Dipeptidase‐1 (DPEP1) is a zinc‐dependent metalloproteinase with multifunctional roles that extend well beyond its classical enzymatic activity in dipeptide hydrolysis. In several cancer types, for example in pancreatic ductal adenocarcinoma, lower DPEP1 expression is associated with higher histological grade, increased invasiveness, chemoresistance, and poorer patient survival, while experimentally increasing its expression suppresses tumor cell invasion and improves drug sensitivity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In colon cancer, DPEP1 appears to exhibit a biphasic function; its early overexpression is observed during adenoma formation and in well‐differentiated carcinomas, yet reduced expression in later stages correlates with enhanced invasiveness and metastatic potential, likely through modulation of leukotriene D4 signaling and regulation of cell adhesion molecules such as E‐cadherin."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the inflammatory setting, DPEP1 has been identified as a novel adhesion receptor on lung and liver endothelium that mediates neutrophil sequestration, thereby contributing to organ inflammation and mortality in endotoxemia; both genetic ablation and functional blocking of DPEP1 markedly reduce neutrophil recruitment and improve survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, DPEP1 plays a critical role in the kidney by virtue of its localization on the tubular brush border where it facilitates the reabsorption and concentration of small peptides and exogenous substances such as radiographic contrast media; this function is a key component of the multi‐step process leading to contrast-induced acute kidney injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond its roles in carcinogenesis and inflammation, DPEP1 has emerged from genetic association studies as a locus linked to variations in plasma homocysteine levels"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "and has been implicated in kidney disease pathogenesis and susceptibility to osteoarthritis and even in B-cell acute lymphoblastic leukemia, where high transcript levels predict poor relapse-free survival."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "11"}]}, {"type": "t", "text": " Moreover, in normal kidney epithelium, DPEP1 is characteristically expressed in differentiated cells and is frequently lost upon cellular transformation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In summary, DPEP1 functions as both an active dipeptidase and as a modulator of cell–cell interactions. Its diverse roles include influencing tumor aggressiveness and metastatic potential, mediating leukocyte adhesion in inflammatory states, and contributing to renal handling of small molecules. Collectively, these functions underscore its potential as a prognostic biomarker and as a therapeutic target in cancer, inflammatory diseases, and kidney injury.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Geng Zhang, Aaron Schetter, Peijun He, et al. 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