Role of Post-Translational Modifications in Pathogenesis of Rheumatoid Arthritis and Therapeutic Targeting: A Comprehensive Systematic Review
Keywords:
Rheumatoid Arthritis, Protein Processing, Post-Translational Modifications, Phosphorylation, Ubiquitination, Acetylation, Autoimmunity, Signal Transduction, CytokineAbstract
Background: Post-translational modifications (PTMs) such as phosphorylation, acetylation, and ubiquitination played a critical role in pathogenesis of inflammatory diseases including rheumatoid arthritis (RA). This systematic review aimed to synthesize evidence of principal role of PTMs in RA and to evaluate the therapeutic potential of agents targeting these dysregulated modification pathways. Methods: This systematic review followed PRISMA guidelines 2020. Research was conducted in PubMed, Scopus, Web of Science, and Google Scholar from 2015 to 2025. The studies which explored the role of particular PTMs in the RA pathophysiology and their therapeutic potential, were considered. Articles and reviews that were not written in English and where mechanistic or therapeutic outcomes were not described were excluded. The JBI Critical Appraisal Checklist, Newcastle-Ottawa Scale, and SYRCLE tool were used for evaluating risk of bias whereas, quality of study was evaluated using GRADE approach. Results: The findings of twelve studies demonstrated that dysregulation of PTMs played a substantial role in RA immunopathology. Mechanistically, acetylation, ubiquitination, and phosphorylation are involved in dysregulated T-cell metabolism, Th17/ Treg imbalance, synovial fibroblast activation, and pro-inflammatory signaling. Preclinical studies supported the therapeutic potential of targeting associated regulatory enzymes. The risk of bias of most studies was measured as moderate and certainty of evidence was found to be low. Conclusion: Phosphorylation, ubiquitination, and acetylation played a critical role in the pathogenesis of RA and could be exploited as potential therapeutic targets.
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