{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Dipeptidyl peptidase 4 (DPP4, also known as CD26) is a multifunctional type II transmembrane serine protease that plays diverse roles in physiology and disease. It has been shown to serve as a functional receptor for certain β‐coronaviruses—for example, mediating infection by human coronavirus–EMC and potentially contributing to COVID-19 pathogenesis via interaction with the viral spike protein—thereby influencing host range and immunomodulation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, DPP4 enzymatic activity critically regulates peptide hormone signaling by cleaving incretins such as glucagon-like peptide 1 (GLP-1), a process that not only terminates canonical receptor-mediated effects but also generates metabolites with distinct cardioprotective actions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Moreover, studies have shown that the tumor suppressor p53 can directly inhibit plasma membrane–associated DPP4 activity, thereby curtailing lipid peroxidation and erastin-induced ferroptosis, which links DPP4 to the control of oxidative stress and cell death."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " DPP4 is also secreted by adipocytes as an adipokine; its elevated release correlates with increased adipocyte size and impaired insulin signaling in peripheral tissues, suggesting an important role in the metabolic syndrome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In the context of cell migration, DPP4 expressed on hematopoietic cells modulates chemotactic responses by cleaving chemokines such as CXCL12/SDF-1α, thereby affecting stem cell homing and immune cell trafficking—a process that can be favorably manipulated by DPP4 inhibition to enhance engraftment and antitumor immunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "9"}]}, {"type": "t", "text": " Finally, high-resolution structural studies of DPP4 have elucidated its substrate-binding cavity and provided crucial insights into its specificity, thereby facilitating the rational design of inhibitors to modulate its activity in various diseases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "V Stalin Raj, Huihui Mou, Saskia L Smits, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dipeptidyl peptidase 4 is a functional receptor for the emerging human coronavirus-EMC."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature12005"}], "href": "https://doi.org/10.1038/nature12005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23486063"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23486063"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Naveen Vankadari, Jacqueline A Wilce "}, {"type": "b", "children": [{"type": "t", "text": "Emerging WuHan (COVID-19) coronavirus: glycan shield and structure prediction of spike glycoprotein and its interaction with human CD26."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Emerg Microbes Infect (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/22221751.2020.1739565"}], "href": "https://doi.org/10.1080/22221751.2020.1739565"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32178593"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32178593"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Kiwon Ban, M Hossein Noyan-Ashraf, Judith Hoefer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circulation (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/CIRCULATIONAHA.107.739938"}], "href": "https://doi.org/10.1161/CIRCULATIONAHA.107.739938"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18427132"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18427132"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Yangchun Xie, Shan Zhu, Xinxin Song, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2017.07.055"}], "href": "https://doi.org/10.1016/j.celrep.2017.07.055"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28813679"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28813679"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Rui Kang, Guido Kroemer, Daolin Tang "}, {"type": "b", "children": [{"type": "t", "text": "The tumor suppressor protein p53 and the ferroptosis network."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Free Radic Biol Med (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.freeradbiomed.2018.05.074"}], "href": "https://doi.org/10.1016/j.freeradbiomed.2018.05.074"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29800655"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29800655"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Daniela Lamers, Susanne Famulla, Nina Wronkowitz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.2337/db10-1707"}], "href": "https://doi.org/10.2337/db10-1707"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21593202"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21593202"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Kent W Christopherson, Giao Hangoc, Charlie R Mantel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Modulation of hematopoietic stem cell homing and engraftment by CD26."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1097071"}], "href": "https://doi.org/10.1126/science.1097071"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15310902"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15310902"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Kent W Christopherson, Giao Hangoc, Hal E Broxmeyer "}, {"type": "b", "children": [{"type": "t", "text": "Cell surface peptidase CD26/dipeptidylpeptidase IV regulates CXCL12/stromal cell-derived factor-1 alpha-mediated chemotaxis of human cord blood CD34+ progenitor cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.169.12.7000"}], "href": "https://doi.org/10.4049/jimmunol.169.12.7000"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12471135"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12471135"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Rosa Barreira da Silva, Melissa E Laird, Nader Yatim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Immunol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ni.3201"}], "href": "https://doi.org/10.1038/ni.3201"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26075911"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26075911"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Hanne B Rasmussen, Sven Branner, Finn C Wiberg, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Crystal structure of human dipeptidyl peptidase IV/CD26 in complex with a substrate analog."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Struct Biol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nsb882"}], "href": "https://doi.org/10.1038/nsb882"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12483204"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12483204"}]}]}]}