Caspase-9 is a cysteine-aspartic protease that plays a critical role as an initiator of the intrinsic apoptosis pathway, also known as the mitochondrial pathway. Caspase-9 is activated in response to various apoptotic stimuli, such as DNA damage, growth factor deprivation, and oxidative stress. It is a key initiator caspase that, once activated, can activate downstream effector caspases like Caspase-3, -6, and -7, leading to the execution of apoptosis. Recent research has revealed that Caspase-9 has functions beyond apoptosis, including the regulation of cellular differentiation/maturation, innate immunity, mitochondrial homeostasis, and autophagy. It has been shown that Caspase-9 can drive neurovascular injury through nonapoptotic endothelial cell dysfunction. Caspase-9 has also been implicated in the regulation of autophagy through its non-apoptotic functions. It maintains mitochondrial homeostasis, which is crucial for the maturation of autophagosomes. Genetic variations in the CASP9 gene have been linked to various diseases, including cancers, neurological disorders, autoimmune pathologies, and lumbar disc disease. Alterations in Caspase-9 expression, activity, or function may be associated with acute and chronic neurodegeneration, retinal neuropathy, and other conditions.
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