{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:21:05Z","timestamp":1790742065883,"version":"4.1.0"},"reference-count":36,"publisher":"IMR Press","issue":"12","license":[{"start":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T00:00:00Z","timestamp":1766534400000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Open Fund of Key Laboratory of Hepatoaplenic Surgery, Ministry of Education, Harbin","award":["GPKF202309"],"award-info":[{"award-number":["GPKF202309"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Front. Biosci. (Landmark Ed)"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.31083\/fbl46505","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T11:51:47Z","timestamp":1767181907000},"source":"Crossref","is-referenced-by-count":1,"title":["AQP9 in Neutrophils Promotes the Formation of NETs by Regulating JAK2-STAT3 Pathway-Mediated Pyroptosis to Aggravate Intestinal Epithelial Cell Injury in Ulcerative Colitis"],"prefix":"10.31083","volume":"30","author":[{"given":"Zetao","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, 150006 Harbin, Heilongjiang, China"},{"name":"Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, 150006 Harbin, Heilongjiang, China"},{"name":"Fifth Department of Medicine (Nephrology\/Endocrinology\/Rheumatology, Pneumonology), University Medical Center Mannheim, University of Heidelberg, 69117 Mannheim, Baden-Wurttemberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, 150006 Harbin, Heilongjiang, China"},{"name":"Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, 150006 Harbin, Heilongjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, 150006 Harbin, Heilongjiang, China"},{"name":"Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, 150006 Harbin, Heilongjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianing","family":"Shi","sequence":"additional","affiliation":[{"name":"Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, 200092 Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2550-6505","authenticated-orcid":true,"given":"Lijun","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The First Affiliated Hospital of Harbin Medical University, 150006 Harbin, Heilongjiang, China"},{"name":"Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, 150006 Harbin, Heilongjiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"16242","published-online":{"date-parts":[[2025,12,24]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","unstructured":"Rawat A, Srivastava R. 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Gasdermin D drives focal crystalline thrombotic microangiopathy by accelerating immunothrombosis and necroinflammation. Blood. 2024; 144: 308\u2013322.","DOI":"10.1182\/blood.2023021949"},{"key":"ref35","doi-asserted-by":"publisher","unstructured":"Huang L, Tan X, Xuan W, Luo Q, Xie L, Xi Y, et al. Ficolin-A\/2 Aggravates Severe Lung Injury through Neutrophil Extracellular Traps Mediated by Gasdermin D-Induced Pyroptosis. The American Journal of Pathology. 2024; 194: 989\u20131006.","DOI":"10.1016\/j.ajpath.2024.02.011"},{"key":"ref36","doi-asserted-by":"publisher","unstructured":"Chen W, Zhao J, Mu D, Wang Z, Liu Q, Zhang Y, et al. Pyroptosis Mediates Neutrophil Extracellular Trap Formation during Bacterial Infection in Zebrafish. Journal of Immunology. 2021; 206: 1913\u20131922.","DOI":"10.4049\/jimmunol.2001335"}],"container-title":["Frontiers in Bioscience-Landmark"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/30\/12\/10.31083\/FBL46505","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T11:36:41Z","timestamp":1767872201000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.imrpress.com\/journal\/FBL\/30\/12\/10.31083\/FBL46505"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,24]]},"references-count":36,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025]]}},"alternative-id":["S2768-6701(25)01533-0"],"URL":"https:\/\/doi.org\/10.31083\/fbl46505","relation":{},"ISSN":["2768-6701","2768-6698"],"issn-type":[{"value":"2768-6701","type":"print"},{"value":"2768-6698","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,24]]},"article-number":"46505"}}