Citrullinated histone H3 (CitH3)

Citrullinated histone H3 (CitH3) is a post-translationally modified protein produced by the enzymatic conversion of arginine residues to citrulline, primarily mediated by peptidylarginine deiminase 4 (PAD4) (Deng et al., 2020) [1]. This modification plays a pivotal role in the formation of neutrophil extracellular traps (NETs) by promoting the decondensation of nuclear chromatin, which is then expelled to capture pathogens (Thålin et al., 2018) [6]. However, when released excessively into the circulation, CitH3 functions as a potent damage-associated molecular pattern (DAMP) that activates pattern recognition receptors, such as TLR2 and TLR4, on endothelial and immune cells (Ouyang et al., 2024) [3]. This activation triggers a cascade of pro-inflammatory cytokines, leading to vascular leakage, microvascular thrombosis, and organ dysfunction (Li et al., 2014) [2]. CitH3 is widely recognized as a prognostic biomarker for sepsis, acute lung injury, and cancer progression (Grilz et al., 2019) [7]. Therapeutic interventions targeting CitH3, including neutralizing monoclonal antibodies and upstream PAD inhibitors, are currently being explored to mitigate the pathological effects of dysregulated NETosis (Pan et al., 2021) [14]. These strategies aim to break the pro-inflammatory feedback loop and improve outcomes in life-threatening inflammatory conditions (Alam et al., 2025) [8]. Preclinical studies have demonstrated that neutralizing CitH3 can significantly improve survival in models of endotoxic shock and sepsis [1, 2].

Other names

H3CitCit-H3Citrullinated H3Histone H3 citrullination

Neutralization of extracellular CitH3 to block pro-inflammatory signaling; inhibition of peptidylarginine deiminase (PAD) enzymes to prevent histone citrullination and NET formation; inhibition of histone deacetylase (HDAC) to suppress CitH3 production.