The multifunctionality of the caspase family of proteases: A new perspective beyond cell death

Abstract

Caspase family proteases, as aspartate-specific cysteine proteases, have long been considered to function exclusively in programmed cell death. However, emerging evidence indicates that their functions extends well beyond apoptosis. Members of this family exhibit numerous non-cell death functions through dynamic regulation of activity gradients and spatiotemporal localization, participating extensively in physiological processes such as neuronal synaptic remodeling, immune homeostasis regulation, and metabolic reprogramming, thereby forming a functional continuum from the molecular to the system level. Based on these novel functions, we propose a function-oriented classification of caspases into three categories: homeostatic, defensive, and remodeling types, while revealing their cross-category functional overlap. In addition, the development of conformation-specific inhibitors and microenvironment-responsive delivery systems provides precise regulatory tools for targeted therapy. This paper systematically summarizes the non-apoptotic functions of the caspase family and proposes a "spatiotemporal activity" dynamic model, opening new avenues for tumor therapy, neurodegenerative disease intervention, and immune disorder regulation.