Gasdermins, Executors of Pyroptosis: A Decade in Perspective

Pyroptosis is a molecularly defined pathway of cell death and lysis relying on formation of membrane pores by the family of gasdermin proteins. Since the characterization of prototypical gasdermin D in 2015, intense effort in the past decade has shed light on protease-dependent activation of these agents of cellular demise in human health and disease, although cell death-independent functions do exist. Numerous regulatory mechanisms ranging from posttranslational modification, control of expression, and overlap in activation systems have been described, but pharmacologic control of gasdermins is still in its infancy. Thus, gasdermin-specific targeting in disease has not yet been achieved outside of a few select cases. This review summarizes these findings broadly from a perspective of biological mechanisms and highlights the forthcoming challenges hindering bench-to-bedside adoption of this knowledge.