Three decades of caspases and RIPKs in life and death.

Caspases and RIPKs are critical regulators of life and death. These molecules have roles in innate immunity and cell death that drive host defense, development, and tumor immunity, but their activation can also contribute to aberrant inflammation and inflammatory disease. This review revisits three decades of genetic studies that have elucidated the critical functions of caspases and RIPKs, synthesizing seminal findings in development, lytic cell death pathways, inflammation, disease pathology, and therapeutic innovation. These studies have led to the paradigm-shifting concept of PANoptosis, defined as an innate immune, inflammatory cell death pathway initiated by innate immune sensors and driven by caspases and RIPKs through PANoptosome complexes. PANoptosis can occur in response to pathogens, pathogen- and damage-associated molecular patterns, homeostatic alterations, cytokines, and the lytic cell death of surrounding cells. Caspase-8 has emerged as a critical core component of PANoptosomes, with other caspases and RIPKs also being key to the molecular activation of PANoptosis. Further genetic studies have established the significance of caspases and RIPKs, including their role in PANoptosis, across the disease spectrum, in infections, inflammatory conditions, cytokine storm, and cancer. Collectively, genetic and biochemical evidence suggests that targeting PANoptosome pathway molecules, including innate immune sensors, caspases, and RIPKs, provides a promising therapeutic strategy for a wide range of conditions, such as neurodegeneration, metabolic disorders, cancers, and chronic inflammatory or autoimmune diseases.