{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:08:46Z","timestamp":1791925726269,"version":"4.3.4"},"reference-count":103,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2023,7,11]],"date-time":"2023-07-11T00:00:00Z","timestamp":1689033600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["91639117"],"award-info":[{"award-number":["91639117"]}]},{"name":"National Natural Science Foundation of China","award":["81941007"],"award-info":[{"award-number":["81941007"]}]},{"name":"National Natural Science Foundation of China","award":["81925005"],"award-info":[{"award-number":["81925005"]}]},{"name":"National Natural Science Foundation of China","award":["81722005"],"award-info":[{"award-number":["81722005"]}]},{"name":"National Natural Science 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Fund","award":["81941007"],"award-info":[{"award-number":["81941007"]}]},{"name":"Sichuan University postdoctoral interdisciplinary Innovation Fund","award":["81925005"],"award-info":[{"award-number":["81925005"]}]},{"name":"Sichuan University postdoctoral interdisciplinary Innovation Fund","award":["81722005"],"award-info":[{"award-number":["81722005"]}]},{"name":"Sichuan University postdoctoral interdisciplinary Innovation Fund","award":["82200084"],"award-info":[{"award-number":["82200084"]}]},{"name":"Sichuan University postdoctoral interdisciplinary Innovation Fund","award":["92268201"],"award-info":[{"award-number":["92268201"]}]},{"name":"Sichuan University postdoctoral interdisciplinary Innovation Fund","award":["91839301"],"award-info":[{"award-number":["91839301"]}]},{"name":"Sichuan University postdoctoral interdisciplinary Innovation Fund","award":["2019JDJQ0030"],"award-info":[{"award-number":["2019JDJQ0030"]}]},{"name":"Sichuan University postdoctoral interdisciplinary Innovation Fund","award":["2019YJ0059"],"award-info":[{"award-number":["2019YJ0059"]}]},{"name":"Sichuan University postdoctoral interdisciplinary Innovation Fund","award":["2023NSFSC0003"],"award-info":[{"award-number":["2023NSFSC0003"]}]},{"name":"Sichuan University postdoctoral interdisciplinary Innovation Fund","award":["2023NSFSC1456"],"award-info":[{"award-number":["2023NSFSC1456"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic liver diseases affect over a billion people worldwide and often lead to fibrosis. Nonalcoholic steatohepatitis (NASH), a disease paralleling a worldwide surge in metabolic syndromes, is characterized by liver fibrosis, and its pathogenesis remains largely unknown, with no effective treatment available. Necroptosis has been implicated in liver fibrosis pathogenesis. However, there is a lack of research on necroptosis specific to certain cell types, particularly the vascular system, in the context of liver fibrosis and NASH. Here, we employed a mouse model of NASH in combination with inducible gene knockout mice to investigate the role of endothelial necroptosis in NASH progression. We found that endothelial cell (EC)-specific knockout of mixed lineage kinase domain-like protein (MLKL), a critical executioner involved in the disruption of cell membranes during necroptosis, alleviated liver fibrosis in the mouse NASH model. Mechanistically, EC-specific deletion of Mlkl mitigated the activation of TGF\u03b2\/Smad 2\/3 pathway, disrupting the pro-fibrotic crosstalk between endothelial cells and hepatic stellate cells (HSCs). Our findings highlight endothelial MLKL as a promising molecular target for developing therapeutic interventions for NASH.<\/jats:p>","DOI":"10.3390\/ijms241411313","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T00:50:41Z","timestamp":1689123041000},"page":"11313","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Targeting Endothelial Necroptosis Disrupts Profibrotic Endothelial\u2013Hepatic Stellate Cells Crosstalk to Alleviate Liver Fibrosis in Nonalcoholic Steatohepatitis"],"prefix":"10.3390","volume":"24","author":[{"given":"Mengli","family":"Yan","sequence":"first","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyu","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyan","family":"Wu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiachen","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengju","family":"Xiao","sequence":"additional","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunheng","family":"Mo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610064, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bi-Sen","family":"Ding","sequence":"additional","affiliation":[{"name":"Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu 610064, China"},{"name":"Fibrosis Research Program, Division of Pulmonary and Critical Care Medicine, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"Division of Regenerative Medicine, Weill Cornell Medicine, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/S2468-1253(18)30077-3","article-title":"Non-alcoholic fatty liver disease and the interface between primary and secondary care","volume":"3","author":"Tsochatzis","year":"2018","journal-title":"Lancet. 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