NINJ1 plays a vital role in the release of neutrophil extracellular traps during acute lung injury PMID: 42350381

ADC Targets in Oncology

2026-04-10

NINJ1 plays a vital role in the release of neutrophil extracellular traps during acute lung injury

Cell Death Dis. 2026 Jun 25. doi: 10.1038/s41419-026-08995-5.

Wen-Jing Zhong ¹ ² ³ , Yu-Biao Liu ² ³ ⁴ , Xin-Yu Yang ² ³ ⁴ , Meng-Rui Chen ² ³ ⁴ , Nan-Shi-Yu Yang ² ³ ⁴ , Chen-Yu Zhang ² ³ ⁴ , Jian-Bing Xiong ⁵ ⁶ , Wei-Feng Tang ⁷ , Cha-Xiang Guan ² ³ ⁸ , Yan-Feng Zhang ¹ ⁵ , Jia-Xi Duan ⁹ ¹⁰ , Yong Zhou ¹¹ ¹² ¹³

Affiliations

1. Department of Geriatric Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China.
2. Department of Physiology, Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan, China.
3. National Experimental Teaching Demonstration Center for Medical Function, Central South University, Changsha, Hunan, China.
4. Key Laboratory of General University of Hunan Province, Basic and Clinical Research in Major Respiratory Disease, Changsha, Hunan, China.
5. National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China.
6. Department of Emergency, Xiangya Hospital, Central South University, Changsha, Hunan, China.
7. Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
8. School of Basic Medicine, Ningxia Medical University, Yinchuan, Ningxia, China.
9. Department of Geriatric Respiratory and Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, China. [email protected].
10. National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. [email protected].
11. Department of Physiology, Xiangya School of Basic Medical Sciences, Central South University, Changsha, Hunan, China. [email protected].
12. National Experimental Teaching Demonstration Center for Medical Function, Central South University, Changsha, Hunan, China. [email protected].
13. Key Laboratory of General University of Hunan Province, Basic and Clinical Research in Major Respiratory Disease, Changsha, Hunan, China. [email protected].

Abstract

Excessive neutrophil extracellular traps (NETs) formation is a significant contributor to acute lung injury (ALI), making its inhibition a novel therapeutic avenue to improve outcomes. In this study, we revealed that a novel pore-forming protein ninjurin-1 (NINJ1) was highly expressed in pro-inflammatory neutrophil subpopulations during ALI, using public single-cell RNA Sequencing and hotspot analysis. Furthermore, we demonstrated that the NINJ1 oligomerization was essential for the NET release in neutrophils from both acute respiratory distress syndrome (ARDS) patients and ALI mice. Genetic ablation of Ninj1 in neutrophils abolished NET release, thereby attenuating pulmonary dysfunction and reducing ALI-related lethality. Mechanistically, we found that K45 and N60 are critical for NINJ1 oligomerization and subsequent NET release. In summary, our findings reveal a novel pore-forming protein-mediated mechanism for NET release and highlight NINJ1 as a potential therapeutic target for the treatment of ALI/ARDS.Schematic illustration. The novel pore-forming protein NINJ1 mediates the extrusion of NETs, thereby exacerbating pulmonary injury in ARDS/ALI. K45 and N60 are essential for NINJ1 oligomerization and subsequent NET release.