Chen Yuchen, Tetz Zoe Ann, Zeng Xindi, Go Sophia Jihye, Ouyang Wenlu, Lee Kyung Eun, Dong Tao, Li Yongqing, Ma Jianjie
Division of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA 22903, USA.
Human Biology DMP, University of Virginia, Charlottesville, VA 22903, USA.
Pharmaceutics. 2025 Jun 23;17(7):809. doi: 10.3390/pharmaceutics17070809.
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.
中性粒细胞是固有免疫的重要组成部分，执行一系列效应功能，包括吞噬作用、脱颗粒以及释放中性粒细胞胞外诱捕网（NETs）。NET形成的一个关键标志是瓜氨酸化组蛋白H3（CitH3）的存在，它由肽基精氨酸脱氨酶（PAD2和PAD4）产生，以促进染色质解聚。虽然NETs发挥着关键的抗菌作用，但过度或失调的NET形成，即NETosis，可在多种疾病中导致组织损伤、慢性炎症和器官功能障碍。除了在NETs中的结构作用外，CitH3还作为一种损伤相关分子模式（DAMP），放大免疫激活和病理性炎症。CitH3水平升高已被确定为脓毒症、病毒感染、缺血再灌注损伤、器官移植、糖尿病伤口、自身免疫性疾病和癌症的生物标志物。尽管人们越来越认识到CitH3的致病作用，但其治疗潜力在很大程度上仍未得到开发。这篇综述总结了在理解CitH3在NETosis和免疫功能障碍中的作用方面的最新进展，强调了针对CitH3的新兴治疗策略，并确定了关键的知识空白。总的来说，这些见解使CitH3成为诊断、预后以及治疗急慢性炎症性疾病的一个有前景的可成药生物标志物。
