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Targeting PAD4: A Promising Strategy to Combat β-Cell Loss in Type 1 Diabetes

Hsu Lin Kang1, András Szász1, Zsuzsanna Valkusz2

  • 1Department of Oral Biology and Experimental Dental Research, Faculty of Dentistry, University of Szeged, 6703 Szeged, Hungary.

International Journal of Molecular Sciences
|July 12, 2025
PubMed

Insights

Peptidylarginine deiminase 4 (PAD4) drives type 1 diabetes mellitus (T1DM) pathogenesis through neutrophil extracellular trap (NET) formation. Inhibiting PAD4 with Cl-amidine reduced NETosis, offering a potential therapeutic strategy for T1DM.

Area of Science:

  • Biochemistry
  • Immunology
  • Endocrinology

Background:

  • Peptidylarginine deiminase 4 (PAD4) catalyzes protein citrullination, a process linked to type 1 diabetes mellitus (T1DM).
  • Understanding PAD4's role in pancreatic inflammation is crucial for T1DM research.

Purpose of the Study:

  • To investigate PAD4 expression and activity in a streptozotocin (STZ)-induced rat model of T1DM.
  • To evaluate the therapeutic potential of a PAD4 inhibitor, Cl-amidine, in mitigating T1DM-associated pancreatic inflammation.

Main Methods:

  • Assessed PAD4 mRNA and protein levels, citrullinated histone H3 (CitH3), calcium, and neutrophil elastase activity in STZ-induced diabetic Wistar rats.
  • Administered Cl-amidine, a pan-PAD inhibitor, to a subset of diabetic rats.
  • Compared findings between diabetic, non-diabetic, and treated groups.

Main Results:

  • Diabetic rats showed elevated PAD4 expression, CitH3 levels, and NETosis markers compared to controls.
  • Pancreatic calcium levels were reduced in diabetic rats, suggesting calcium consumption during PAD4 activation.
  • Cl-amidine treatment effectively attenuated NETosis in diabetic rats.

Conclusions:

  • PAD4 activation and subsequent NETosis are implicated in the pathogenesis of T1DM.
  • STZ-induced diabetic rats serve as a valuable model for studying PAD4's role in T1DM.
  • Cl-amidine demonstrates therapeutic promise for reducing pancreatic inflammation in T1DM.
Keywords:
PAD4STZWistar rat

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