Targeting cluster of differentiation 26 / dipeptidyl peptidase 4 (CD26/DPP4) in organ fibrosis

Abstract

Cluster of differentiation 26 (CD26)/dipeptidyl peptidase 4 (DPP4) is an exopeptidase that is expressed as a transmembrane protein in many organs but also present in a circulating soluble form. Beyond its enzymatic and costimulatory activity, CD26/DPP4 is involved in the pathogenesis of chronic fibrotic diseases across many organ types, such as liver cirrhosis, kidney fibrosis and lung fibrosis. Organ fibrosis is associated with a high morbidity and mortality, and there are no causative therapies that can effectively attenuate the progress of the disease. Growing evidence suggests that inhibiting CD26/DPP4 can modulate the profibrotic tissue microenvironment and thus reduce fibrotic changes within affected organs. This review summarizes the role of CD26/DPP4 in fibroproliferative disorders and highlights new opportunities for an antifibrotic treatment by CD26/DPP4 inhibition. As a major advantage, CD26/DPP4 inhibitors have been in safe and routine clinical use in type 2 diabetes for many years and thus qualify for repurposing to repurpose as a promising therapeutic against fibrosis.

Functional roles of CD26/DPP4 in bleomycin‐induced pulmonary fibrosis

“…One review paper mentions that the inhibition of CD26/DPP4 may regulate TGF‐β production in a disease‐specific manner mainly depending on the cell type that are involved. CD26/DPP4 inhibition has no major effects on systemic TGF‐β levels; however, it generally results in a local reduction of TGF‐β expression in fibrotic disease (Ohm et al, 2022 ). Taken together with the results in the current study, these studies suggest a close link among CD26/DPP4, regulation of TGF‐β expression, and lung fibroblast activation.…”

Therapeutic targets of fibrosis: Translational advances and current challenges

“…Remodelling is a key characteristic in organs targeted by disease, where deposition of collagen and extracellular matrix can lead to organ failure. As illustrated in our Figure 1, Ohm et al (2023) have reviewed those cells involved in fibrosis development and organ impairment and considered the role of CD26 and its dipeptidyl peptidase‐4 (DPP4) activity in fibroproliferative disorders, putting forward CD26/DPP4 inhibition as a potential antifibrotic treatment for multiple organs (in particular lung, heart, liver, kidney and skin) (Alexander et al, 2021).…”

“…Overview of reported antifibrotic mechanisms reported in preclinical models for CD26/dipeptidyl peptidase 4 (DPP4) inhibition, as reviewed by Ohm et al (2023) (figure reproduced from their review in this special themed issue). EMT, epithelial‐to‐mesenchymal transition; EndoMT, endothelial‐to‐mesenchymal transition.…”

“…Ohm and colleagues propose here that DPP4 inhibitors may be repurposed as a promising therapeutic approach against fibrosis of multiple organs, considering the potential utility of CD26/DPP4 inhibition as therapeutics for renal fibrosis/injury, hepatic fibrosis/steatohepatitis, cardiomyopathy, pulmonary fibrosis, scleroderma and cutaneous wound healing and scar formation. With DPP4 inhibitors in current clinical use, the authors set forth that CD26/DPP4 inhibitors potentially offer the promise of halting excess extracellular matrix deposition and allowing for tissue repair in multiple organ systems (Ohm et al, 2023).…”

“…Remodelling is a key characteristic in organs targeted by disease, where deposition of collagen and extracellular matrix can lead to organ failure. As illustrated in our Figure 1 inhibitors potentially offer the promise of halting excess extracellular matrix deposition and allowing for tissue repair in multiple organ systems (Ohm et al, 2023).…”