Dipeptidyl peptidase 4
Dipeptidyl peptidase 4
Overview
Dipeptidyl peptidase 4 (DPP-4), also known as CD26, is a serine protease and type II transmembrane glycoprotein expressed ubiquitously across multiple tissues including the kidney, liver, intestine, immune cells, and endothelial surfaces. Its primary enzymatic function is to cleave dipeptides from the N-terminus of proline- or alanine-containing Peptides, a mechanism that positions it as a central regulator of several metabolically and cardiovascularly important signaling molecules. Most notably, DPP-4 rapidly degrades glucagon-like peptide-1 (GLP-1) and related incretin Peptides, which are key mediators of postprandial insulin secretion and glucose homeostasis. By truncating GLP-1 within minutes of its release from intestinal L-cells, DPP-4 substantially attenuates its insulinotropic and cytoprotective effects, making the enzyme an important aggravating factor in the progression and exacerbation of type 2 diabetes mellitus. Beyond glycemic regulation, DPP-4 has emerged as a multifunctional protease with roles in cardiovascular protection, bone metabolism, neurodegeneration, and inflammation — reflecting the broad physiological significance of its substrates.
DPP-4 exists in both membrane-anchored and soluble circulating forms, and its activity is elevated in individuals with obesity, insulin resistance, and arterial hypertension. The pharmacological inhibition of DPP-4 — through a class of orally administered drugs known as gliptins — has become a well-established strategy for managing type 2 diabetes, with agents such as sitagliptin and vildagliptin widely used in clinical practice. Emerging research is broadening the understanding of DPP-4 beyond its canonical metabolic role, revealing its involvement in cardiac ischemia, intervertebral disc degeneration, bone senescence, and neurodegenerative conditions such as Parkinson's disease.
Focus of Latest Publications
Recent publications on dipeptidyl peptidase 4 (DPP4) continue to center on its role in glucose homeostasis and type 2 diabetes, while also expanding into broader cardiometabolic, neuroinflammatory, skeletal, and degenerative disease contexts. Several studies focused on developing or evaluating DPP4-directed inhibitors and degraders, including structure-based de novo dual DPP IV/PTP1B inhibitor design, PROTAC-mediated DPP-4 degradation, and the antidiabetic DPP4 inhibitors linagliptin and sitagliptin. These reports collectively emphasize DPP4 as a therapeutic target for sustained glycemic control, with one PROTAC study showing prolonged blood glucose reduction and GLP-1 elevation after a single dose, and another reporting that sitagliptin attenuated intervertebral disc degeneration through macrophage–nucleus pulposus cell crosstalk.
A substantial portion of the recent literature explored natural products and food-derived peptides as DPP4 inhibitors. Garlic-derived peptides, walnut meal peptides, and Lentinula edodes stem-derived peptides were identified through integrated workflows combining digestion simulation, peptidomics, molecular docking, molecular dynamics, network pharmacology, and in situ or cell-based validation. These studies reported DPP4 inhibitory activity for multiple peptides, with some candidates retaining activity after simulated gastrointestinal digestion and enhancing active GLP-1 secretion in enteroendocrine cells. Similar screening approaches were also applied to Chinese herbal preparations, where separated fractions from Sanhuang Xiexin Decoction showed DPP-4 inhibitory activity, supporting the search for natural DPP4 inhibitors.
Beyond diabetes, DPP4 was implicated in disease mechanisms involving oxidative stress, ferroptosis, inflammation, and tissue injury. In senile osteoporosis models, galangin was reported to suppress DPP4 nuclear translocation and its interaction with NOX1, thereby blocking reactive oxygen species-dependent ferroptosis signaling and rescuing bone marrow stromal cell senescence. In multiple sclerosis-related analyses, genetically predicted DPP4 activity was associated with disease susceptibility, and DPP4 silencing partially restored endothelial barrier integrity and reduced inflammatory signaling in experimental models exposed to nicotine-derived nitrosamine ketone. In cardiac ischemia/reperfusion injury, a gut microbiota-derived DPP4 isozyme from Bacteroides acidifaciens degraded cardioprotective peptides such as GLP-1 and worsened myocardial injury, while pharmacological inhibition of the microbial enzyme mitigated dysfunction.
Other studies extended DPP4 research into cardiovascular and neurodegenerative settings. Linagliptin was evaluated in a large animal model of cardiometabolic syndrome for effects on coronary microvascular function and collateralization, reflecting interest in DPP4 inhibition beyond glycemic endpoints. A saxagliptin-derived Schiff base series was investigated in a streptozotocin-induced Alzheimer-like model, where selected derivatives improved oxidative, amyloidogenic, and cholinergic dysfunction, with one compound showing particularly strong multi-pathway activity. Together, these publications portray DPP4 as a versatile target at the intersection of metabolism, inflammation, and tissue remodeling, with ongoing efforts spanning small-molecule inhibition, targeted degradation, natural peptide discovery, and mechanistic studies of DPP4-linked pathology.