Caspase-9: A Multimodal Therapeutic Target With Diverse Cellular Expression in Human Disease.

Caspase-9, a cysteine-aspartic protease known for its role as an initiator of intrinsic apoptosis, regulates physiological cell death and pathological tissue degeneration. Its nonapoptotic functions, including regulation of cellular differentiation/maturation, innate immunity, mitochondrial homeostasis, and autophagy, reveal a multimodal landscape of caspase-9 functions in health and disease. Recent work has demonstrated that caspase-9 can drive neurovascular injury through nonapoptotic endothelial cell dysfunction. polymorphisms have been linked with various cancers, neurological disorders, autoimmune pathologies and lumbar disc disease. Clinical reports suggest alterations in caspase-9 expression, activity or function may be associated with acute and chronic neurodegeneration, retinal neuropathy, slow-channel myasthenic syndrome, lumbar disc disease, cardiomyopathies, atherosclerosis and autoimmune disease. Healthy tissues maintain caspase-9 activity at low basal levels, rendering supraphysiological caspase-9 activation a tractable target for therapeutic interventions. Strategies for selective inhibition of caspase-9 include dominant negative caspase-9 mutants and pharmacological inhibitors derived from the XIAP protein, whose Bir3 domain is an endogenous highly selective caspase-9 inhibitor. However, the mechanistic implications of caspase-9 expression and activation remain indeterminate in many pathologies. By assembling clinical reports of caspase-9 genetics, signaling and cellular localization in human tissues, this review identifies gaps between experimental and clinical studies on caspase-9, and presents opportunities for further investigations to examine the consequences of caspase activity in human disease.