Mapping benefit, risk, and opportunity in PAD4 inhibition

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…