Caspase-8, Caspase-9, and Caspase-3 (CASP8/9/3)

Caspase-8, Caspase-9, and Caspase-3 are essential cysteine-aspartic proteases that constitute the core machinery of the apoptotic cascade [1, 2]. Caspase-8 and Caspase-9 function as initiator caspases, activated via the extrinsic (death receptor) and intrinsic (mitochondrial) pathways, respectively [1, 9]. These initiators then cleave and activate Caspase-3, the primary executioner caspase responsible for the systematic dismantling of cellular components, leading to the morphological hallmarks of apoptosis [1, 18]. In therapeutic contexts, these enzymes are targeted for inhibition to treat neurodegenerative diseases, traumatic brain injury, and liver disorders where excessive apoptosis causes tissue loss [1, 3, 11]. Conversely, in oncology, therapeutic strategies aim to activate these caspases to overcome the evasion of apoptosis, a hallmark of cancer [2, 9, 10]. Drugs such as emricasan act as pan-caspase inhibitors to preserve cell viability, while agents like PAC-1 or TRAIL-receptor agonists are designed to trigger the cascade to eliminate malignant cells [2, 10, 11].

Other names

Apoptotic caspase cascadeCaspase-8 (FLICE)Caspase-9 (MCH6)Caspase-3 (CPP32)Cysteine-aspartic acid protease 8/9/3

Drugs targeting these caspases typically act as either irreversible or reversible inhibitors to prevent cell death in degenerative conditions, or as activators (either directly or by inhibiting endogenous inhibitors like XIAP) to induce apoptosis in cancer cells [2, 3, 5, 10].