Systematic review indicates diverse viruses exploit host peptidylarginine deiminase isoforms to subvert immunity and enhance replication.

Peptidylarginine deiminases (PADs) are calcium-dependent enzymes that catalyze protein citrullination, a post-translational modification implicated in both physiological processes and the pathogenesis of various diseases. This review provides a systematic overview of the PAD family's roles in viral infections, with a focus on their tissue distribution, activation mechanisms, and functional significance in host-pathogen interactions. Accumulating evidence indicates that diverse viruses have evolved to exploit specific host PAD isoforms as a strategy to subvert antiviral immunity and enhance viral replication. This review delves into the intricate interplay between viruses and the PAD family, detailing how distinct viruses selectively upregulate or hijack particular PAD isoforms to disrupt host immune defenses. We further compare the divergent strategies employed by DNA and RNA viruses in leveraging PAD-mediated citrullination and summarize the therapeutic potential of PAD inhibitors, such as GSK484 and Cl-amidine, in antiviral interventions. Additionally, demethoxycurcumin (DMC), as the only identified selective small-molecule activator of PAD2 to date, provides a valuable tool for investigating the role of PAD2-mediated citrullination in viral infection. Finally, we discuss current research limitations and propose future directions aimed at deciphering the complex virus-PAD-host axis, with the ultimate goal of informing the development of novel antiviral therapeutics.