AQP9 in neutrophils promotes the formation of NETs by regulating JAK2-STAT3 pathway-mediated pyroptosis to aggravate intestinal epithelial cell injury in ulcerative colitis
Background: Ulcerative colitis (UC) is a chronic inflammatory disorder primarily affecting the rectum and colon. This study aimed to identify potential therapeutic targets that may inhibit UC progression and mitigate patient suffering. Methods: UC-related datasets were retrieved from the Gene Expres...
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| Main Authors: | , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
24 December 2025
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| In: |
Frontiers in bioscience. Landmark
Year: 2025, Volume: 30, Issue: 12, Pages: 1-18 |
| ISSN: | 2768-6698 |
| DOI: | 10.31083/FBL46505 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.31083/FBL46505 Verlag, kostenfrei, Volltext: https://www.imrpress.com/journal/FBL/30/12/10.31083/FBL46505 
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| Author Notes: | Zetao Wang, Yao Sun, Xiaohui Zhou, Jianing Shi, Lijun Shi, Zetao Wang, Yao Sun, Xiaohui Zhou, Jianing Shi, Lijun Shi |
| Summary: | Background: Ulcerative colitis (UC) is a chronic inflammatory disorder primarily affecting the rectum and colon. This study aimed to identify potential therapeutic targets that may inhibit UC progression and mitigate patient suffering. Methods: UC-related datasets were retrieved from the Gene Expression Omnibus database. Differential expression analysis, weighted gene co-expression network analysis, immunoinfiltration analysis, and pyroptosis scoring were employed to identify key pyroptosis-related genes implicated in UC pathogenesis. A dextran sulfate sodium salt (DSS)-induced mouse model of UC was established, and neutrophil extracellular traps (NETs) were induced in neutrophils by stimulation with phorbol 12-myristate 13-acetate (PMA). Histopathological changes in mouse colon tissues were assessed by hematoxylin-eosin staining, and NET formation was evaluated via immunofluorescence. The expression of aquaporin 9 (AQP9), peptidylarginine deiminase 4 (PAD4), zonula occludens 1 (ZO-1), occludin, and proteins related to pyroptosis and the JAK2-STAT3 pathway was determined by Western blotting. Levels of inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA), production of reactive oxygen species was assessed using fluorescent probes, and intestinal epithelial cell viability and death were evaluated using the cell counting kit-8 (CCK-8) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays, respectively. Results: Five hub genes (AQP9, S100A8, S100A9, S100A12, and VNN2) were identified through bioinformatics analysis, with AQP9 selected for further investigation. Single-cell analysis and immunofluorescence revealed that AQP9 was predominantly expressed in neutrophils and upregulated in the colon tissues of mice with UC and PMA-stimulated neutrophils. Knockdown of AQP9 in PMA-treated neutrophils led to suppression of the JAK2-STAT3 pathway, reduced pyroptosis, and decreased NET formation. Upon co-culture with intestinal epithelial cells, AQP9 knockdown resulted in enhanced epithelial cell viability, reduced apoptosis, and upregulation of ZO-1 and occludin. Conversely, treatment of neutrophils from the PMA+si-AQP9 with a JAK2-STAT3 pathway agonist increased pyroptosis, enhanced the formation of NETs, and induced epithelial cell injury. Similarly, treatment with a pyroptosis agonist enhanced both pyroptosis and the formation of NETs, further aggravating epithelial damage. Conclusion: Knockdown of AQP9 inhibits JAK2-STAT3 pathway-mediated pyroptosis, thereby reducing the formation of NETs and attenuating intestinal epithelial cell injury. |
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| Item Description: | Gesehen am 19.02.2026 |
| Physical Description: | Online Resource |
| ISSN: | 2768-6698 |
| DOI: | 10.31083/FBL46505 |