Peptidylarginine deiminase 4 (PAD4) is increasingly targeted to modulate inflammatory pathology, yet its inhibition produces biological effects that extend beyond the processes it was originally designed to suppress. While PAD4 targeting has largely been pursued to limit neutrophil extracellular trap (NET) formation, accumulating data indicate that PAD4 activity also shapes immune regulation through citrullination of non-histone substrates, with consequences for antigen presentation, cytokine function, and adaptive immune activation. These broader effects introduce important considerations for translation, as PAD4 inhibition can simultaneously attenuate tissue-damaging inflammation and undermine protective host responses. In this review, we examine PAD4 targeting through a benefit–risk–opportunity framework that integrates enzymatic specificity, cellular context, and disease setting. We discuss how suppression of NET-driven pathology underlies therapeutic benefit in thrombo-inflammatory disease, how impaired control of microbial dissemination represents a central risk in infection, and how direct effects on dendritic- and T-cell-mediated responses may be leveraged in autoimmune contexts. Rather than reflecting unintended drug activity, many immune effects attributed to off-target inhibition arise from disruption of citrullination-dependent regulatory pathways. This perspective provides a mechanistic basis for selecting indications, designing combination strategies, and defining appropriate safety endpoints, supporting a more precise and context-aware approach to PAD4 targeting in immune-mediated disease.
Bonilha et al. (Thu,) studied this question.