Preeclampsia (PE) is considered as a disease of placental origin. However, the specific mechanism of placental abnormalities remains elusive. This study identified thrombospondinâ1 (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 damageâassociated molecular patterns (DAMPs). Necroptosis inhibitors necrostatinâ1 and GSKâ˛872 restore the trophoblast survival while panâcaspase inhibitor ZâVADâFMK has no effect. Mechanistically, the results show that THBS1 interacts with transforming growth factor Bâactivated kinase 1 (TAK1), which is a central modulator of necroptosis quiescence and affects its stability. Moreover, THBS1 silencing upâregulates the expression of neuronal precursor cellâexpressed developmentally downâregulated 4 (NEDD4), which acts as an E3 ligase of TAK1 and catalyzes K48âlinked ubiquitination of TAK1 in HTR8/SVneo cells. Besides, THBS1 attenuates PE phenotypes and improves the placental necroptosis in vivo. Taken together, the downâregulation of THBS1 destabilizes TAK1 by activating NEDD4âmediated, K48âlinked TAK1 ubiquitination and promotes necroptosis and DAMPs release in trophoblast cells, thus participating in the pathogenesis of PE.