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Review
. 2025 Jul 31;29(1):340.
doi: 10.1186/s13054-025-05545-x.

Targeting high circulating dipeptidyl peptidase 3 in circulatory failure

Adrien Picod  1   2   3 , Feriel Azibani  4 , Veli-Pekka Harjola  5 , Mahir Karakas  6   7 , Antoine Kimmoun  8   9   10 , Bruno Levy  8   9   10 , Peter Pickkers  11 , Holger Thiele  12 , Uwe Zeymer  13 , Karine Santos  14 , Alexandre Mebazaa  4   15
Affiliations
Review

Targeting high circulating dipeptidyl peptidase 3 in circulatory failure

Adrien Picod et al. Crit Care. .

Abstract

Circulating dipeptidyl peptidase 3 is a new biomarker linked to circulatory failure prognosis and pathophysiology and is a potential actionable therapeutic target. In this short review intended for the clinician, a question-and-answer format provides key insights on the nature of this biomarker and the therapeutical potential of its targeted inhibition in critically ill patients.

Supplementary Information: The online version contains supplementary material available at 10.1186/s13054-025-05545-x.

Keywords: Angiotensin II; Cardiogenic shock; Circulatory failure; Dipeptidyl peptidase 3; Renin-angiotensin-aldosterone system; Sepsis; Septic shock.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: AP reports having received research grants from the Société de Réanimation de Langue Française (SRLF), the Société Française d’Anesthésie Réanimation (SFAR), the Zoll Fondation, the Fonds pour la chirurgie cardiaque and 4TEEN4 Pharmaceuticals GmbH. MK is supported by the Else Kroener-Fresenius-Stiftung (W3 Else Kroener Clinician Scientist Professorship). He reports grant and non-financial support from Adrenomed AG and CSL Vifor, as well as personal fees from Adrenomed AG, Sphingotec GmbH, CSL Vifor, Daiichi-Sankyo, Pharmacosmos and 4TEEN4 Pharmaceuticals GmbH. PP has received research grants, travel and consultancy reimbursements from 4TEEN4 Pharmaceuticals GmbH. UZ received speaker honoraria form 4TEEN4 Pharmaceuticals. KS is employed as chief scientific officer at 4TEEN4 Pharmaceuticals GmbH. AM reports personal fees from Orion, Roche, Adrenomed and Fire 1, and grants and personal fees from 4TEEN4 Pharmaceuticals GmbH, Abbott, Roche, and Sphingotec GmbH.

Figures

Fig. 1
Fig. 1
Current understanding of the mode of action of cDPP3 and procizumab in circulatory failure. The upper part of the figure illustrates the pathogenic effects of high cDPP3, which excessively cleave angiotensin II, contributing to vasodilation, hypotension, and acute kidney injury. The lower part depicts the therapeutic action of procizumab, which inhibits cDPP3 activity, preserves angiotensin II, thereby stabilizing systemic and renal hemodynamics. (c)DPP3: (circulating) dipeptidyl peptidase 3
Fig. 2
Fig. 2
Distribution of circulating dipeptidyl peptidase 3 (cDPP3) concentration across cohorts of ambulatory individuals with relative frequency indicating the proportion of individual in each population with a given cDPP3 concentration (A), influence of sex (B) and age (C). The “healthy” population (n = 120) consists of individuals who are free of detectable pathology and are not receiving any medication. The “reference” population (n = 8,849) includes ambulatory individuals who may present with comorbidities and chronic treatments, reflecting the baseline characteristics of patients likely to be admitted to the intensive care unit. Details about cohorts included in this analysis can be found in the supplemental table. cDPP3: circulating dipeptidyl peptidase 3
Fig. 3
Fig. 3
Distribution of circulating dipeptidyl peptidase 3 (cDPP3) concentration and its association with clinical outcomes in patients with circulatory failure, based on a meta-analysis of seven studies (1,310 patients): relative frequency of individuals in each populations with a given cDPP3 concentration, and proportion (%) of patients higher than the 30 ng/ml cut-off corresponding to the 95th percentile of a reference population (A), survival (B) and need for organ support (C) according to cDPP3. Patients who did not survive were systematically categorized as having required organ support. Details about cohorts included in this analysis can be found in the supplemental table. cDPP3: circulating dipeptidyl peptidase 3; RRT: Renal replacement therapy
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References

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