The study investigates the role of ZBP1 and TRIF in necroptosis, a form of programmed cell death, in mice lacking caspase-8 and TNFR1. Using immunohistochemistry (IHC) and in situ hybridization (ISH), the researchers characterized the expression patterns of RIPK1, RIPK3, Mlk1, and ZBP1 in various mouse tissues. They found that RIPK1, RIPK3, and Mlk1 were co-expressed in immune cells, endothelial cells, and many epithelial tissues, while ZBP1 showed more variable expression, particularly in epithelial cells. Notably, ZBP1 expression was elevated in Casp8−/− Tnfr1−/− embryos before their death from aberrant necroptosis around embryonic day 15 (E15). Deletion of Zbp1 in these embryos prolonged their survival, suggesting that ZBP1 contributes to embryonic lethality. Additionally, TRIF contributed to perinatal lethality in Casp8−/− Tnfr1−/− Zbp1−/− mice, indicating that TRIF-induced necroptosis plays a role in postnatal development. The study highlights the complex interplay between RIPK1, RIPK3, Mlk1, and ZBP1 in necroptosis and their roles in embryonic and perinatal development.The study investigates the role of ZBP1 and TRIF in necroptosis, a form of programmed cell death, in mice lacking caspase-8 and TNFR1. Using immunohistochemistry (IHC) and in situ hybridization (ISH), the researchers characterized the expression patterns of RIPK1, RIPK3, Mlk1, and ZBP1 in various mouse tissues. They found that RIPK1, RIPK3, and Mlk1 were co-expressed in immune cells, endothelial cells, and many epithelial tissues, while ZBP1 showed more variable expression, particularly in epithelial cells. Notably, ZBP1 expression was elevated in Casp8−/− Tnfr1−/− embryos before their death from aberrant necroptosis around embryonic day 15 (E15). Deletion of Zbp1 in these embryos prolonged their survival, suggesting that ZBP1 contributes to embryonic lethality. Additionally, TRIF contributed to perinatal lethality in Casp8−/− Tnfr1−/− Zbp1−/− mice, indicating that TRIF-induced necroptosis plays a role in postnatal development. The study highlights the complex interplay between RIPK1, RIPK3, Mlk1, and ZBP1 in necroptosis and their roles in embryonic and perinatal development.