PANoptosis components, regulation, and implications

microbial infections to activate programmed cell death (PCD) pathways. Pyroptosis, apoptosis, and necroptosis are three key PCD pathways characterized by their molecular and genetic features. Dysregulation of these pathways promotes disease, including aging-related autoimmune and neurodegenerative diseases and cancer. While early studies of cell death focused on the unique genetic programs and biochemical functions that comprise each of these individual mechanisms, recent studies indicate remarkable crosstalk and redundancies among them. Our studies have connected the inflammasome sensors, caspase-1, and caspase-11 (components of pyroptosis) with caspase-8, caspase-7, and PARP (components of apoptosis), and RIPK1 and RIPK3 (components of necroptosis). These discoveries laid the foundation for us to pioneer the concept of PANoptosis [1], which we define as the integration of the pyroptosis, apoptosis, and necroptosis pathways into a unified mechanism of inflammatory cell death. Understanding the regulation and evolutionary relevance of PANoptosis in health and disease is key to identifying ways to globally modulate these processes for disease prevention and treatment.