Gasdermins: New Therapeutic Targets in Host Defense, Inflammatory Diseases, and Cancer

Abstract

Gasdermins (GSDMs) are a class of pore-forming proteins related to pyroptosis, a programmed cell death pathway that is induced by a range of inflammatory stimuli. Small-scale GSDM activation and pore formation allow the passive release of cytokines, such as IL-1β and IL-18, and alarmins, but, whenever numerous GSDM pores are assembled, osmotic lysis and cell death occur. Such GSDM-mediated pyroptosis promotes pathogen clearance and can help restore homeostasis, but recent studies have revealed that dysregulated pyroptosis is at the root of many inflammation-mediated disease conditions. Moreover, new homeostatic functions for gasdermins are beginning to be revealed. Here, we review the newly discovered mechanisms of GSDM activation and their prominent roles in host defense and human diseases associated with chronic inflammation. We also highlight the potential of targeting GSDMs as a new therapeutic approach to combat chronic inflammatory diseases and cancer and how we might overcome the current obstacles to realize this potential.

Antagonistic nanobodies reveal mechanism of GSDMD pore formation and unexpected therapeutic potential

“…GSDMD is a highly sought-after drug target, although the development of specific GSDMD inhibitors was not successful to date [44][45][46][47] . Therapeutic application of the potent pyroptosisinhibiting nanobodies described in this study would require efficient delivery of nanobodies into the cytosol of target cells.…”

Escherichia coli K88 activates NLRP3 inflammasome-mediated pyroptosis in vitro and in vivo

“…During extended exposure to various antigens including pathogens and toxins, the sensitive and fragile intestinal homeostasis can be disturbed [ 32 ]. Specifically, the host can activate immune response, intestinal inflammation, and cell death against inflammatory stimuli [ 33 ]. Pyroptosis is one of programmed cell death modes necessary for the innate immune system to fight against intracellular pathogens by preventing pathogen replication and exposing pathogens to extracellular killing mechanisms [ 34 ].…”

A novel risk score model based on pyroptosis-related genes for predicting survival and immunogenic landscape in hepatocellular carcinoma

“…The essential components of pyroptosis, including inflammasomes, GSDM proteins and cytokines, are all associated with the development, invasion and metastasis of tumors [ 15 ]. Cleavage of GSDM family members, such as GSDMD and GSDME, mediated by cysteine proteases is the key process that causes pyroptosis [ 38 ]. Previous studies have shown that GSDME is downregulated in some human cancers and might act as a tumor suppressor [ 39 , 40 ].…”