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However, the specific mechanism of placental abnormalities remains elusive. This study identified thrombospondin\u20101 (THBS1) is downregulated in preeclamptic placentae and negatively correlated with blood pressure. Functional studies show that THBS1 knockdown inhibits proliferation, migration, and invasion and increases the cycle arrest and apoptosis rate of HTR8\/SVneo cells. Importantly, THBS1 silencing induces necroptosis in HTR8\/SVneo cells, accompanied by the release of damage\u2010associated molecular patterns (DAMPs). Necroptosis inhibitors necrostatin\u20101 and GSK\u2032872 restore the trophoblast survival while pan\u2010caspase inhibitor Z\u2010VAD\u2010FMK has no effect. Mechanistically, the results show that THBS1 interacts with transforming growth factor B\u2010activated kinase 1 (TAK1), which is a central modulator of necroptosis quiescence and affects its stability. Moreover, THBS1 silencing up\u2010regulates the expression of neuronal precursor cell\u2010expressed developmentally down\u2010regulated 4 (NEDD4), which acts as an E3 ligase of TAK1 and catalyzes K48\u2010linked ubiquitination of TAK1 in HTR8\/SVneo cells. Besides, THBS1 attenuates PE phenotypes and improves the placental necroptosis in vivo. Taken together, the down\u2010regulation of THBS1 destabilizes TAK1 by activating NEDD4\u2010mediated, K48\u2010linked TAK1 ubiquitination and promotes necroptosis and DAMPs release in trophoblast cells, thus participating in the pathogenesis of PE.<\/jats:p>","DOI":"10.1002\/advs.202309002","type":"journal-article","created":{"date-parts":[[2024,4,3]],"date-time":"2024-04-03T18:37:28Z","timestamp":1712169448000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Thrombospondin\u20101 Regulates Trophoblast Necroptosis via NEDD4\u2010Mediated Ubiquitination of TAK1 in Preeclampsia"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2706-0321","authenticated-orcid":false,"given":"Haoyue","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology Nanfang Hospital Southern Medical University  Guangzhou Guangdong 510515 China"},{"name":"Guangzhou Key Laboratory of Forensic Multi\u2010Omics for Precision Identification School of Forensic Medicine Southern Medical University  Guangzhou Guangdong 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Nanfang Hospital Southern Medical University  Guangzhou Guangdong 510515 China"},{"name":"Guangzhou Key Laboratory of Forensic Multi\u2010Omics for Precision Identification School of Forensic Medicine Southern Medical University  Guangzhou Guangdong 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Nanfang Hospital Southern Medical University  Guangzhou Guangdong 510515 China"},{"name":"Guangzhou Key Laboratory of Forensic Multi\u2010Omics for Precision Identification School of Forensic Medicine Southern Medical University  Guangzhou Guangdong 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rixuan","family":"Feng","sequence":"additional","affiliation":[{"name":"School of Nursing Southern Medical University  Guangzhou Guangdong 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenling","family":"Luo","sequence":"additional","affiliation":[{"name":"School of Nursing Southern Medical University  Guangzhou Guangdong 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology School of Public Health Southern Medical University  Guangzhou Guangdong 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zixin","family":"Tao","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology Guangzhou First People's Hospital School of Medicine South China University of Technology  Guangzhou Guangdong 510180 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology; 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