Targeting peptidyl-arginine deiminase 4 suppresses SARS-CoV-2 replication and modulates the inflammatory response

SARS-CoV-2, the causative agent of COVID-19, remains a global concern due to gaps in understanding its pathogenesis. Peptidyl-arginine deiminases (PADs) are emerging as key regulators of viral replication and inflammation. PADs catalyze the conversion of arginine into citrulline, a modification linked to autoimmune diseases. Here, we show that PAD-mediated citrullination plays a crucial role in SARS-CoV-2 infection. Using human cell lines and in K18-hACE2 transgenic mice infected with different SARS-CoV-2 strains, we demonstrate that viral replication is associated with increased PAD4 expression. Mass spectrometry shows 170 distinct differentially citrullinated proteins in infected cells and tissues. Importantly, PAD4 inhibition significantly reduces viral replication and restores a citrullination profile comparable to that of uninfected mice. These findings suggest that SARS-CoV-2 exploits PAD-mediated citrullination to enhance replication and inflammation. Thus, targeting PAD4 may represent a viable strategy to curb viral spread and mitigate COVID-19-associated hyperinflammation.