Dipeptidyl peptidase 4 (DPP-4)

Dipeptidyl peptidase 4 (DPP-4), also known as CD26 or adenosine deaminase complexing protein 2, is a serine protease and type II transmembrane glycoprotein expressed across many tissues, including the kidney, liver, intestine, immune cells, and vascular endothelium. It also circulates in a soluble form shed from cell membranes. Its enzymatic function is to cleave dipeptides from the N-terminus of peptides that carry a proline or alanine at the penultimate position, an activity that lets it regulate the availability of numerous bioactive peptides. Most prominently, DPP-4 rapidly inactivates the incretin hormone glucagon-like peptide-1 (GLP-1), truncating it within minutes of its release from intestinal L-cells and thereby blunting its insulinotropic effect on postprandial glucose control. Because of this, elevated or unchecked DPP-4 activity is regarded as an aggravating factor in the progression of type 2 diabetes, and DPP-4 expression and activity are frequently increased in the setting of obesity and insulin resistance.

This substrate-truncating mechanism makes DPP-4 a validated pharmacological target. The "gliptin" class of orally administered inhibitors — including sitagliptin, vildagliptin, saxagliptin, and linagliptin — blocks the enzyme's active site, prolonging endogenous GLP-1 signaling to improve glycemic control in type 2 diabetes, and newer strategies such as PROTAC-mediated targeted degradation aim to achieve more sustained suppression than reversible inhibition allows. Beyond glucose homeostasis, DPP-4 and its inhibition are being examined in a widening range of contexts: coronary microvascular function and cardiovascular disease, bone metabolism and cellular senescence, where DPP-4 has been linked to ferroptosis in bone marrow stromal cells, neurodegenerative and diabetes-associated cognitive pathology, and even primary ovarian failure. These connections reflect the breadth of DPP-4's substrates and its intersections with oxidative stress, inflammatory signaling involving mediators such as Tnf-α, and iron-dependent cell death pathways.