One Enzyme, Many Faces: The Expanding Role of DPP3 in Cardiovascular and Critical Care

Dipeptidyl peptidase 3 (DPP3) is a zinc-dependent aminopeptidase that is found in several places and is thought to be a cytosolic enzyme that helps break down peptides. Recent studies, however, have revealed its extensive therapeutic relevance upon release into circulation, functioning not only as a biomarker for cellular injury but also as an active modulator of cardiovascular homeostasis and critical disease. High levels of circulating DPP3 (cDPP3) have been linked to the causes of cardiogenic shock, septic shock, acute coronary syndromes, heart failure, and serious viral diseases like COVID-19. Its enzymatic breakdown of angiotensin II disrupts vascular tone and myocardial contractility, leading to hemodynamic instability and multi-organ failure. In numerous cohorts, cDPP3 levels reliably correspond with disease severity, acute renal damage, and death, but dynamic trajectories yield superior predictive information relative to single assessments. In addition to risk stratification, translational studies utilizing rodent and porcine models illustrate that antibody-mediated inhibition of cDPP3 with the humanized monoclonal antibody Procizumab reinstates cardiac function, stabilizes renal perfusion, diminishes oxidative stress and inflammation, and enhances survival. First-in-human experiences in patients with refractory septic cardiomyopathy have further emphasized its therapeutic promise. DPP3 is a good example of a biomarker and a mediator in cardiovascular and critical care. Its growing clinical and translational profile makes cDPP3 a strong predictor of bad outcomes and a prospective target for treatment. Ongoing clinical trials using Procizumab will determine if neutralizing cDPP3 can lead to enhanced outcomes in individuals with cardiogenic and septic shock. This review outlines the physiological mechanisms, clinical implications, and emerging therapeutic potential of DPP3 in cardiovascular and critical care. Ongoing trials with Procizumab will clarify whether neutralizing cDPP3 can improve outcomes in patients with cardiogenic and septic shock.