Caspase 8

Caspase 8 is an initiator protease of death receptor-mediated extrinsic apoptosis and also supports cell survival by restraining RIP-family kinase-dependent necroptosis^[1]. Mechanistically, caspase 8 works with cFLIP to regulate the switch among survival, apoptosis, and necroptosis, while cFLIP is structurally related to caspase 8 but lacks proteolytic activity^[1][2]. Therefore, caspase 8 differs from inflammatory caspases such as caspase 1, 4, 5, and 12, which participate in inflammasome-related innate immune responses^[3]. In intestinal disease, caspase 8 controls Paneth cell necroptosis and may contribute to epithelial cell death and mucosal inflammation in Crohn’s disease^[3]. In severe SARS-CoV-2 mouse models, non-apoptotic caspase 8 promoted cytokine release, IL-1β elevation, NF-κB-linked inflammation, and disease pathology^[4]. In ovarian cancer, low caspase 8 expression correlated with shorter overall survival, while caspase 8 loss enhanced non-apoptotic necroptotic death under NF-κB blockade^[5]. For experimental applications, studies use genetic caspase 8 loss, viral caspase 8 inhibitors, and necroptosis pathway modulation to separate apoptosis, inflammation, and RIPK3-MLKL-dependent cell death^[6].