CitH3, a Druggable Biomarker for Human Diseases Associated with Acute NETosis and Chronic Immune Dysfunction
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 peptidyla...
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| author | Yuchen Chen Zoe Ann Tetz Xindi Zeng Sophia Jihye Go Wenlu Ouyang Kyung Eun Lee Tao Dong Yongqing Li Jianjie Ma |
| author_facet | Yuchen Chen Zoe Ann Tetz Xindi Zeng Sophia Jihye Go Wenlu Ouyang Kyung Eun Lee Tao Dong Yongqing Li Jianjie Ma |
| author_sort | Yuchen Chen |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-2920edd4f5534e9c9791dad48e2e8317 |
| institution | Kabale University |
| issn | 1999-4923 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj-art-2920edd4f5534e9c9791dad48e2e83172025-08-20T03:56:46ZengMDPI AGPharmaceutics1999-49232025-06-0117780910.3390/pharmaceutics17070809CitH3, a Druggable Biomarker for Human Diseases Associated with Acute NETosis and Chronic Immune DysfunctionYuchen Chen0Zoe Ann Tetz1Xindi Zeng2Sophia Jihye Go3Wenlu Ouyang4Kyung Eun Lee5Tao Dong6Yongqing Li7Jianjie Ma8Division of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA 22903, USADivision of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA 22903, USADivision of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA 22903, USADivision of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA 22903, USADepartment of Surgery, University of Michigan Health System, Ann Arbor, MI 48109, USADivision of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA 22903, USADepartment of Surgery, University of Michigan Health System, Ann Arbor, MI 48109, USADepartment of Surgery, University of Michigan Health System, Ann Arbor, MI 48109, USADivision of Surgical Sciences, Department of Surgery, University of Virginia, Charlottesville, VA 22903, USANeutrophils 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.https://www.mdpi.com/1999-4923/17/7/809sepsisinfectioninflammationischemia–reperfusion injurywound healingautoimmune diseases |
| spellingShingle | Yuchen Chen Zoe Ann Tetz Xindi Zeng Sophia Jihye Go Wenlu Ouyang Kyung Eun Lee Tao Dong Yongqing Li Jianjie Ma CitH3, a Druggable Biomarker for Human Diseases Associated with Acute NETosis and Chronic Immune Dysfunction Pharmaceutics sepsis infection inflammation ischemia–reperfusion injury wound healing autoimmune diseases |
| title | CitH3, a Druggable Biomarker for Human Diseases Associated with Acute NETosis and Chronic Immune Dysfunction |
| title_full | CitH3, a Druggable Biomarker for Human Diseases Associated with Acute NETosis and Chronic Immune Dysfunction |
| title_fullStr | CitH3, a Druggable Biomarker for Human Diseases Associated with Acute NETosis and Chronic Immune Dysfunction |
| title_full_unstemmed | CitH3, a Druggable Biomarker for Human Diseases Associated with Acute NETosis and Chronic Immune Dysfunction |
| title_short | CitH3, a Druggable Biomarker for Human Diseases Associated with Acute NETosis and Chronic Immune Dysfunction |
| title_sort | cith3 a druggable biomarker for human diseases associated with acute netosis and chronic immune dysfunction |
| topic | sepsis infection inflammation ischemia–reperfusion injury wound healing autoimmune diseases |
| url | https://www.mdpi.com/1999-4923/17/7/809 |
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