Targeting Protein Arginine Deiminases in Rheumatoid Arthritis: Pathophysiology and Therapeutic Progress

Yung-Chieh Huang^1,2,3, Wen-Chien Cheng^4,5, Ya-Hsuan Chao⁶, Tzu-Ting Chen^7,*, Chi-Chen Lin^8,9,10,11,*
1 Division of Allergy, Immunology and Rheumatology, Department of Pediatrics, Taichung Veterans General Hospital, Taichung, 407, Taiwan
2 Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, 402, Taiwan
3 Doctoral Program in Translational Medicine, National Chung Hsing University, Taichung, 402, Taiwan
4 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, 402, Taiwan
5 School of Medicine, College of Medicine, China Medical University, Taichung, 402, Taiwan
6 Department of Material Science and Engineering, National Chiao Tung University, Hsinchu, 30010, Taiwan
7 Institute of Bioinformatics and Structural Biology & Department of Medical Sciences, National Tsing Hua University, Hsinchu, 300, Taiwan
8 Department of Medical Research, China Medical University Hospital, Taichung, 402, Taiwan
9 Department of Medical Research, Taichung Veterans General Hospital, Taichung, 402, Taiwan
10 Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
11 Institute of Biomedical Science, National Chung-Hsing University, Taichung, 402, Taiwan
* Corresponding Author: Tzu-Ting Chen. Email: email ; Chi-Chen Lin. Email: email
(This article belongs to the Special Issue: Natural and Synthetic Small Molecules in the Regulation of Immune Cell Functions)

BIOCELL https://doi.org/10.32604/biocell.2025.072732

Received 02 September 2025; Accepted 02 December 2025; Published online 29 December 2025

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Abstract

Protein arginine deiminases (PADs) are key enzymes in the development of rheumatoid arthritis (RA), catalyzing the conversion of arginine to citrulline in a process called citrullination. This post-translational modification is crucial to RA pathogenesis as it creates neo-antigens that trigger the production of anti-citrullinated protein antibodies (ACPAs). These ACPAs are highly specific to RA and often appear before clinical symptoms, making them valuable biomarkers for diagnosis and prognosis. Beyond ACPA production, PADs, particularly PAD4, play a vital role in forming neutrophil extracellular traps (NETs). NETs contribute to inflammation and joint damage, further highlighting the importance of PAD activity in the disease. The dysregulation of PADs is not limited to joint inflammation but also contributes to systemic complications of RA, such as cardiovascular and pulmonary disorders like interstitial lung disease (ILD). Citrullination of proteins in various tissues may contribute to these complications by generating autoantigens or disrupting tissue structures. Targeting PADs with small-molecule inhibitors or monoclonal antibodies shows promise in preclinical studies, with compounds like Cl-amidine and isozyme-selective inhibitors like GSK199 demonstrating efficacy in animal models. However, challenges remain in drug development, including limited isozyme specificity, off-target effects, and the complexity of citrullination networks, which hinder clinical translation. Overcoming these obstacles will require a multidisciplinary approach to optimize drug design and validate PADs as effective therapeutic targets for improving RA management and mitigating its systemic effects. The purpose of this review is to summarize the current understanding of the multifaceted roles of PADs in RA, from pathogenesis and systemic complications to the status and challenges of therapeutic development.