Caspase-8 and caspase-9 (CASP8/9)

Caspase-8 and Caspase-9 are the primary initiator caspases that orchestrate the commencement of programmed cell death, or apoptosis, through the extrinsic and intrinsic pathways, respectively (UniProt Q14790, P55211). Caspase-8 is typically activated by extracellular ligands binding to death receptors like FAS or TNFR1, leading to the assembly of the death-inducing signaling complex (DISC) (NIH StatPearls). In contrast, Caspase-9 is triggered by internal cellular stress, such as DNA damage or oxidative stress, which causes mitochondrial outer membrane permeabilization and the release of cytochrome c to form the apoptosome (PubMed: 1.2.1). Both enzymes are cysteine-aspartic proteases that, once activated, cleave and activate executioner caspases like Caspase-3 and Caspase-7 to carry out the final stages of cell dismantling (UniProt). These proteins are critical therapeutic targets; in oncology, drugs like Smac mimetics and BH3 mimetics aim to restore their activity to kill tumor cells, while in inflammatory and neurodegenerative diseases, inhibitors like emricasan are studied to prevent excessive cell loss (PubMed: 1.2.2). However, a significant challenge in targeting these caspases is the potential for cells to switch to necroptosis, a pro-inflammatory form of cell death, when apoptotic pathways are blocked (PubMed: 1.1.1).

Other names

Initiator caspasesApoptotic initiator caspasesCaspase-8 (FLICE/MACH/Mch5)Caspase-9 (Mch6/ICE-LAP6/APAF-3)

Inhibition of cysteine protease activity or activation of the apoptotic cascade through death receptor or mitochondrial pathways.