Neutrophils are essential components of innate immunity, executing a range of effector functions including phagocytosis, degranulation, and the release of neutrophil extracellular traps (NETs). A key hallmark of NET formation is the presence of citrullinated histone H3 (CitH3), produced by peptidylarginine deiminases (PAD2 and PAD4) to facilitate chromatin decondensation. While NETs play critical antimicrobial roles, excessive or dysregulated NET formation, termed NETosis, can drive tissue injury, chronic inflammation, and organ dysfunction across a wide spectrum of diseases. Beyond its structural role within NETs, CitH3 acts as a damage-associated molecular pattern (DAMP), amplifying immune activation and pathological inflammation. Elevated CitH3 levels have been identified as biomarkers in sepsis, viral infections, ischemia–reperfusion injury, organ transplantation, diabetic wounds, autoimmune diseases, and cancer. Despite increasing recognition of CitH3’s pathogenic contributions, its therapeutic potential remains largely untapped. This review summarizes recent advances in understanding the role of CitH3 in NETosis and immune dysfunction, highlights emerging strategies targeting CitH3 therapeutically, and identifies critical knowledge gaps. Collectively, these insights position CitH3 as a promising druggable biomarker for the diagnosis, prognosis, and treatment of acute and chronic inflammatory diseases.

Sepsis-induced acute lung injury (ALI) is prevalent in patients with sepsis and has a high mortality rate. Peptidyl arginine deiminase 2 (PADI2) and PADI4 play crucial roles in mediating the host’s immune response in sepsis, but their specific functions remain unclear. Our study shows that Padi2 ^–/– Padi4 ^–/– double KO (DKO) improved survival, reduced lung injury, and decreased bacterial load in Pseudomonas aeruginosa (PA) pneumonia–induced sepsis mice. Using single-cell RNA-Seq (scRNA-Seq), we found that the deletion of Padi2 and Padi4 reduced the Nlrp3 ⁺ proinflammatory macrophages and fostered Chil3 ⁺ myeloid cell differentiation into antiinflammatory macrophages. Additionally, we observed the regulatory role of the NLRP3/Ym1 axis upon DKO, confirmed by Chil3 knockdown and Nlrp3 -KO experiments. Thus, eliminating Padi2 and Padi4 enhanced the polarization of Ym1 ⁺ M2 macrophages by suppressing NLRP3, aiding in inflammation resolution and lung tissue repair. This study unveils the PADIs/NLRP3/Ym1 pathway as a potential target in treatment of sepsis-induced ALI.

Ischemia/reperfusion (I/R) injury causes myocardial damage, and Ginkgolide C (GC), a component of Ginkgo biloba, shows potential for cardioprotection. However, its effects on I/R-induced cardiac dysfunction and mechanisms are unclear. This study evaluates GC preconditioning in rats, focusing on its impact on cardiac function, myocardial injury, and the PI3K/Akt pathway. GC preconditioning was assessed using an isolated rat heart model of I/R injury. Cardiac function (LVDP, LVEDP, +dp/dtmax, dp/dtmax), infarct size, histopathological changes, injury, and oxidative stress markers were measured. Rat cardiomyocytes were treated with GC to assess viability, contraction, and apoptosis. Molecular docking and protein analysis explored GC's interaction with the Akt pathway. GC preconditioning significantly improved cardiac function, with a marked enhancement in LVDP, +dp/dtmax, and -dp/dtmax in the GC50 group compared to the I/R group (P<0.01). GC treatment also reduced myocardial infarct size (14.8 %±2.4 % vs. 25.5 %±1.9 %, P<0.01), decreased LDH release, and alleviated histopathological damage, including myocyte necrosis and inflammatory infiltration. Furthermore, GC significantly improved cardiomyocyte viability and contraction amplitude, particularly at 50 μM. At the molecular level, GC activated the Akt pathway, as evidenced by increased p-Akt expression. Co-treatment with the PI3K inhibitor LY294002 reversed the protective effects of GC, confirming the involvement of the Akt pathway. Additionally, GC preconditioning reduced oxidative stress, as indicated by enhanced SOD activity and decreased levels of myocardial injury markers (LDH, CK-MB), and decreased apoptosis, reflected by a lower Bax/Bcl-2 ratio. GC preconditioning reduces I/R-induced myocardial injury in rats by activating the PI3K/Akt pathway, reducing oxidative stress, inhibiting apoptosis, and improving cell viability. These results support GC's potential for treating ischemic heart disease and suggest Akt-targeted interventions for myocardial protection.