CASP8 (caspase 8) is a crucial cysteine protease that serves as an initiator caspase in the extrinsic apoptotic pathway 1. The protein is synthesized as an inactive pro-caspase and becomes activated through cleavage reactions, functioning as a main effector of apoptotic cell death 1. CASP8 plays a central role in death receptor-mediated apoptosis, being immediately recruited to oligomerized Fas receptors where its protease activity is essential for the apoptotic response generated by the death-inducing signaling complex (DISC) 2. In TNF receptor signaling, CASP8 participates in a two-step process where it associates with FADD in a cytoplasmic complex (complex II) that determines cell fate - when NF-κB survival signals fail, this complex triggers apoptosis 3. The protein can also be activated through RHIM-driven recruitment mechanisms involving RIP proteins, forming caspase-8-FADD-cFLIP complexes 4. CASP8 demonstrates involvement in oocyte apoptosis during oogenesis, where Fas ligand binding activates caspase 8, leading to either direct executioner caspase activation or mitochondrial-mediated apoptosis through Bid cleavage 5. Polymorphisms in CASP8 show significant associations with cancer susceptibility, with certain variants providing protective effects against various cancers including ovarian, breast, and colorectal cancers 67.