Caspase 6

Caspase-6 (CASP6) is a cysteine-aspartate protease traditionally classified as an executioner caspase that participates in apoptotic signaling and substrate cleavage during programmed cell death^[1][2]. Mechanistically, caspase-6 functions within the broader caspase network that regulates apoptosis, inflammation, and cellular homeostasis, and accumulating evidence demonstrates that its biological activities extend beyond classical apoptotic execution^[1][3]. In innate immune pathways, caspase-6 promotes inflammasome activation and facilitates the assembly of the ZBP1-PANoptosome, thereby supporting pyroptotic, apoptotic, and necroptotic signaling collectively termed PANoptosis^[3]. During influenza A virus infection, caspase-6 enhances the interaction between RIPK3 and ZBP1, contributing to inflammatory cell death, cytokine production, and host defense responses^[3]. Disease relevance is further supported by studies linking caspase-6 activity to neurodegenerative disorders, including Alzheimer’s disease and Huntington’s disease, where aberrant caspase-6 activation has been associated with pathological processes independent of overt apoptosis^[2][4]. Compared with the closely related executioner caspases caspase-3 and caspase-7, caspase-6 displays distinct biological functions, including non-enzymatic regulation of innate immune signaling and PANoptosome-associated pathways, highlighting functional divergence within the executioner caspase subgroup^[1][3]. For experimental applications, the development of isoform-selective caspase-6 inhibitors has attracted significant interest because selective modulation of caspase-6 may enable mechanistic studies while reducing off-target effects associated with broad-spectrum caspase inhibition^[5].