Gasdermin D: A Potential New Auxiliary Pan-Biomarker for the Detection and Diagnosis of Diseases

Abstract

Pyroptosis is a form of programmed cell death mediated by gasdermins, particularly gasdermin D (GSDMD), which is widely expressed in tissues throughout the body. GSDMD belongs to the gasdermin family, which is expressed in a variety of cell types including epithelial cells and immune cells. It is involved in the regulation of anti-inflammatory responses, leading to its differential expression in a wide range of diseases. In this review, we provide an overview of the current understanding of the major activation mechanisms and effector pathways of GSDMD. Subsequently, we examine the importance and role of GSDMD in different diseases, highlighting its potential as a pan-biomarker. We specifically focus on the biological characteristics of GSDMD in several diseases and its promising role in diagnosis, early detection, and differential diagnosis. Furthermore, we discuss the application of GSDMD in predicting prognosis and monitoring treatment efficacy in cancer. This review proposes a new strategy to guide therapeutic decision-making and suggests potential directions for further research into GSDMD.

Keywords: biomarker; diagnostic; gasdermin D; pyroptosis.

Figure 1

The process of pyroptosis involving gasdermin A (GSDMA), gasdermin B (GSDMB), gasdermin C (GSDMC), gasdermin D (GSDMD), and gasdermin E (GSDME). The toll-like receptor recognizes LPS, bacteria, and viruses and leads to the activation of caspases. Caspase cleaves gasdermins into N-terminal and C-terminal fragments. GSDMD-N binds to cardiolipin, forming transmembrane pores and causing cell lysis and cytokine release. Other GSDMs can also lead to pyroptosis.

Figure 2

Overview of GSDMD expression according to the Human Protein Atlas [31]. The grayscale representation in the figure indicates the weighted annotation of cellular protein levels based on GSDM transcript levels in normal tissues, extracted from the HPA RNA-seq dataset within the Human Protein Atlas. Meanwhile, the color-coded depiction represents the weighted annotation of the proportion of patients exhibiting moderate to strong cytoplasmic and membranous immune reactivity in cancer tissue. Immunohistochemistry staining using 3,3′-diaminobenzidine substrate linked to horseradish peroxidase is employed to visualize the tissue sections, which are then counterstained with hematoxylin to enhance the microscopic features.

Figure 3

The process of GSDMD in the pathogenesis of preeclampsia. High sugar environments, toxic substances, uric acid, and fatty acids act as risk factors, transmitting information to the cell nucleus, activating the NFκB signaling pathway to increase the expression of NLRP3, Pro-IL1β, and Pro-IL-18, while also activating mitochondria to release ROS and NO. TLR can recognize LPS, transmit signals to NLRP3, and activate GSDMD and cytokines. Activated cytokines, GSDMD, ROS, and NO together activate the inflammatory cascade reaction.

Figure 4

The process of GSDMD in the pathogenesis of systemic onfection. SARS-CoV-2 can overactivate NLRP3 through the binding of the spike protein and ACE2 while also causing the activation of the adrenaline–angiotensin–aldosterone system and complement cascade. SARS-CoV-2 can also activate MAC through the MBL-MASP-2 pathway, leading to the binding of NLRP3 and ultimately activating GSDMD. Activated GSDMD and caspase-11 have also been found in neutrophil extracellular traps, activating the DIC cascade reaction through the activation of tissue factor and phosphatidic acid.

Figure 5

The role of GSDMD in pancreatic cancer pathogenesis. Chemotherapy drugs such as 5-FU can enter the cell nucleus and regulate the expression of NLRP3, AIM2, NCLR4, GSDMD, and cytokine precursors, thereby increasing the activation of GSDMD and upregulating the function of CD8+ T cells and NK cells.