{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T04:20:14Z","timestamp":1792383614711,"version":"4.4.0"},"reference-count":45,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T00:00:00Z","timestamp":1724284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100012543","name":"Science and Technology Innovation Plan of the Shanghai Science and Technology Commission","doi-asserted-by":"publisher","award":["22Y11907400"],"award-info":[{"award-number":["22Y11907400"]}],"id":[{"id":"10.13039\/100012543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012543","name":"Science and Technology Innovation Plan of the Shanghai Science and Technology Commission","doi-asserted-by":"publisher","award":["23ZR1410100"],"award-info":[{"award-number":["23ZR1410100"]}],"id":[{"id":"10.13039\/100012543","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Natural Science Foundation of Shanghai","award":["22Y11907400"],"award-info":[{"award-number":["22Y11907400"]}]},{"name":"the Natural Science Foundation of Shanghai","award":["23ZR1410100"],"award-info":[{"award-number":["23ZR1410100"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Portal vein thrombosis (PVT) is a challenging and controversial complication of cirrhosis. Experimental models that reproduce cirrhotic PVT and effective pharmacological therapies are limited. We aimed to investigate the nature course and mechanisms of PVT in cirrhosis. A novel PVT model was developed via two-step total portal vein ligation in healthy and thioacetamide (TAA)-cirrhotic rats. Circulating and liver-infiltrating neutrophils were isolated from individuals with cirrhosis to examine neutrophil extracellular traps (NETs) and explore their unique characteristics and implications in PVT-associated fibrosis in cirrhosis. We further validated macrophage\u2013myofibroblast transition (MMT) via multiplex immunofluorescence and single-cell sequencing. In the experimental model, cirrhosis promoted PVT development and portal vein intimal thickening. Interestingly, cirrhosis promoted spontaneous resolution of PVT due to instability of thrombus structure, along with pulmonary and intrahepatic clots. NETs-MMT mediate cirrhotic PVT and PVT-associated fibrosis, including fibrotic thrombus remodeling and increased hepatic collagen deposition. Mechanistically, caspase-4-dependent activation of neutrophils and GSDMD mediated the formation of NETs. The extracellular DNA of NETs promoted TGF-\u03b21\/Smad3-driven MMT. Inhibiting GSDMD with disulfiram suppressed cirrhotic PVT and prevented associated fibrosis. The cirrhotic PVT model reflected the following three main characteristics of cirrhotic PVT: spontaneous resolution, immunothrombosis, and intimal fibrosis. Targeting NETs with GSDMD inhibitors may serve as a new therapeutic concept to treat cirrhotic PVT.<\/jats:p>","DOI":"10.3390\/ijms25169099","type":"journal-article","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T05:16:24Z","timestamp":1724649384000},"page":"9099","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["GSDMD-Dependent Neutrophil Extracellular Traps Mediate Portal Vein Thrombosis and Associated Fibrosis in Cirrhosis"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4878-375X","authenticated-orcid":false,"given":"Ying","family":"Che","sequence":"first","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youjung","family":"Chien","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuli","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoquan","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Ai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China"},{"name":"Center of Evidence-Based Medicine, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"759","DOI":"10.3892\/etm.2021.10191","article-title":"Portal vein thrombosis: A concise review","volume":"22","author":"Costache","year":"2021","journal-title":"Exp. 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