Peptidylarginine deiminase 4-mediated citrullination in human disease: molecular mechanisms and therapeutic targeting.

Peptidylarginine deiminase 4 (PAD4) is a calcium-dependent enzyme that catalyzes protein citrullination, a post-translational modification that can alter protein charge, conformation, and function. Among the mammalian peptidylarginine deiminase isoforms, PAD4 is distinguished by its nuclear localization, its ability to citrullinate histones, and its established roles in chromatin remodeling, transcriptional control, and neutrophil extracellular trap formation. Through these activities, PAD4 links epigenetic regulation with innate immunity, inflammation, and thrombosis. Dysregulated PAD4 activity has been implicated in rheumatoid arthritis systemic lupus erythematosus central nervous system demyelinating disease, cancer, atherosclerosis, acute thrombotic syndromes, and sepsis. Mechanistically, PAD4-mediated citrullination influences chromatin accessibility, inflammatory signaling, autoantigen generation, extracellular matrix remodeling, and immunothrombosis. These observations have made PAD4 an attractive pharmacological target. Drug development has progressed from early irreversible inhibitors, including Cl-amidine and F-amidine, to more selective reversible compounds such as GSK484 and GSK199, as well as newer orally available candidates such as JBI-589 and JBI-1044. Emerging approaches, including allosteric ligands, cyclic peptides, and functional antibodies, continue to broaden the PAD4-targeting landscape. In this review, we summarize the molecular basis of PAD4-mediated citrullination, examine its contributions to major disease settings, evaluate current and emerging PAD4-directed therapies, and discuss the key challenges that must be addressed for successful clinical translation.