The recently discovered Gasdermin (GSDM) protein family plays a crucial role in regulating pyroptosis, a special form of programmed cell death (PCD). In humans, six homologous genes have been identified: GSDMA-E and DFNB59. The role of GSDMs in pyroptosis has been confirmed, and GSDMA-E has been shown to undergo protein hydrolysis processing, leading to the release of n-terminal (NT) fragments that assemble into pores on the plasma membrane (PM).
These GSDM pores can penetrate PM and mitochondrial membranes, leading to inflammatory cell death. In addition, they promote the extracellular secretion of cytokines such as inflammatory cytokines and mitochondrial DNA (mtDNA), which are known to be involved in the pathogenesis of many diseases.
Our Featured Products
In GSDMs, GSDMD has always been a widely studied topic, initially believed to be a key mediator of inflammation-induced pyroptosis. In addition, it is highly involved in various disease-related inflammations. After activation of GSDMD, the connecting region can be cleaved by caspase-1/11 (human caspase-1/4/5), separating GSDMD-nt from the self-inhibitory domain GSDMD-ct. GSDMD-NT forms transmembrane pores, releases cytokines such as interleukin-1 (IL)-1Ī² and IL-18, and can disrupt the homeostasis of ions and water, which may exacerbate the progression of various inflammations.
GSDMs are becoming attractive checkpoints for immune response, inflammation, cancer, and autoimmune diseases, and they are also involved in many systemic diseases. In recent years, significant progress has been made in the development of small molecule inhibitors targeting GSDMD. Several GSDMD inhibitors alleviated the pathology of preclinical disease models.
The encouraging results have accelerated the pace of developing GSDMD inhibitors, from preclinical research to human trials. Therefore, it is crucial to study the functions and mechanisms of novel GSDMs in a range of diseases, as well as their potential clinical applications. Understanding which GSDMD inhibitors should be prioritized in trials targeting specific disease indications has become particularly urgent.
Recently, researchers from the Naval Medical University published a review article titled “The Gasdermin family: emerging therapeutic targets in diseases” in the Journal of Signal Transmission and Targeted Therapy, revealing that the Gasdermin family is a newly emerging therapeutic target for diseases.
The Gasdermin (GSDM) family has attracted great attention due to its role as a key participant in pyroptosis in immunity and diseases. A recently discovered class of pore formation effector proteins play a crucial role in processes such as membrane permeation, pyroptosis, and subsequent inflammatory responses, which are important self-defense mechanisms against stimuli and infections.
GSDMs are associated with a range of diseases, including but not limited to sepsis, viral infections, and cancer, whether through involvement in pyroptosis or independent of this process. Regulating GSDM-mediated apoptosis as a promising therapeutic strategy for various diseases is gaining recognition.
The current strategies for inhibiting GSDMD mainly include binding to GSDMD, blocking GSDMD cleavage, or inhibiting GSDMD n-terminal (NT) oligomerization, although there are some off-target effects. In this review, researchers delved into the cutting-edge understanding of the interaction between GSDMs and apoptosis, elucidated the activation mechanism of GSDMs, explored their association with a range of diseases, and discussed the latest advances and potential strategies of GSDMD inhibitors.
In short, pyroptosis, as a mode of PCD, is associated with various inflammations. Since GSDMs are an emerging research field, the more specific functions of GSDMs in inflammation and corresponding diseases still need to be elucidated. Therefore, further animal experiments and clinical trials are needed to further investigate and confirm the effects and potential mechanisms of GSDMs. Furthermore, considering more complex factors when seeking to discover and develop more effective GSDM inhibitors would be beneficial and enlightening.
Related Products and Services
Protein Expression and Purification Services
Reference
Chenglong Zhu et al. The gasdermin family: emerging therapeutic targets in diseases. Signal Transduct Target Ther.2024 Apr 8;9(1):87. doi: 10.1038/s41392-024-01801-8.