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

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 animalmodels.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.