Gasdermin D in Sepsis: The Potential to Block Pyroptosis and Challenges for Clinical Use
Background
Gasdermin D (GSDMD), which executes pyroptosis, an inflammatory form of cell death, is being studied as a therapeutic target to reduce organ injury in sepsis. A review published in Frontiers in Immunology summarizes GSDMD’s mechanisms and therapeutic strategies. It does not report results from a new trial in patients; evidence for the effects of the inhibitory strategies discussed comes mainly from preclinical studies.
Sepsis is a condition in which a severely dysregulated host response to infection causes life-threatening organ dysfunction. Alongside reducing pathogens with antibiotics, attention must also be paid to how an excessive immune response leads to tissue damage. GSDMD is a protein that forms pores in cell membranes and contributes to the release of inflammatory mediators and cell death. It has drawn attention as one mechanism linking infection to systemic injury.
Key findings
Danger signals from pathogens or damaged tissues can activate the canonical pathway, which involves caspase-1. In the noncanonical pathway, human caspases-4 and -5 or mouse caspase-11 detect lipopolysaccharide (LPS) in the cytosol. Both pathways lead to GSDMD cleavage, and the released N-terminal fragments assemble in the cell membrane to form pores. The review explains that this process contributes to the release of inflammatory cytokines, including interleukin-1β and interleukin-18, and to the amplification of inflammation.
The review also summarizes patterns of injury in different organs. In the lungs, pyroptosis of alveolar macrophages intensifies inflammation. In the liver, the review describes a pathway in which the release of high-mobility group box 1 (HMGB1) contributes to the amplification of systemic inflammation. It also discusses kidney microthrombi and damage to the blood–brain barrier in the context of GSDMD-related mechanisms. However, findings from different cell and animal models cannot be applied identically to all patients with sepsis.
The review presents disulfiram as a therapeutic candidate that modifies the Cys191 residue of human GSDMD, blocking the assembly of proteins into pores. Anti-GSDMD antibodies represent a separate preclinical strategy. The review also describes a preclinical approach combining the antibiotic imipenem with disulfiram. This combination aims both to clear pathogens and to suppress excessive host inflammation, but this does not mean that therapeutic efficacy has been established in people with sepsis.
Implications and outlook
The challenge of targeting GSDMD is deciding not only how strongly to inhibit it, but also in which cells and when. Pyroptosis also contributes to defense against infection, so prolonged inhibition could interfere with bacterial clearance. The review identifies the timing of interventions according to immune status and organ- and cell-specific drug delivery as major challenges for clinical translation.
The review also discusses measuring GSDMD cleavage products in blood to distinguish patients’ immune states. However, clinical measurement methods have not been standardized, and validation in large patient cohorts remains necessary. A particular concentration cannot readily be used as a direct criterion for administering treatment or presented as an established treatment guideline. Using single-cell analysis and machine learning to predict treatment response is likewise a proposed direction for future research; the review does not provide a validated prediction algorithm or training dataset.
These mechanisms and limitations are summarized in the review on GSDMD and sepsis.
Sepsis is a life-threatening organ dysfunction that leads to 11 million annual global deaths. It is characterized by severe immune dysregulation, with gasdermin D (GSDMD)-driven pyroptosis recognized as a key pathogenic mechanism. After exposure to pathogen-associated molecular patterns (PAMPs)/damage-associated molecular patterns (DAMPs), GSDMD, activated via the canonical (caspase-1) and non-canonical (caspase-4/5/11) pathways, forms plasma membrane pores, induces cell lysis, and triggers multi-organ injury. Specifically, GSDMD pores trigger lung inflammation via alveolar macrophage pyroptosis, induce hepatic high mobility group box 1 protein (HMGB1) release, perpetuate bacteremia, cause renal microthrombosis, and disrupt the blood-brain barrier. GSDMD drives both the hyperinflammatory phase (via cytokine storm, NETosis) and the immunosuppressive phase (via lymphocyte apoptosis, T-cell exhaustion), thereby defining hyperinflammatory (GSDMD-NT >120 ng/mL) and immunosuppressive (intestinal barrier failure) endotypes. Promising therapeutic agents include disulfiram (blocking Cys191 oligomerization), anti-GSDMD mAb26.5 (decreasing mortality to 30%), and the combination of imipenem and disulfiram. Clinical translation faces challenges in terms of biomarker validation, organ-specific delivery, and phase-adapted intervention. Future research directions include AI-based drug design, exosome-mediated CRISPR knockout, clinical trials on drug repurposing, and single-cell omics-integrated stratified immunotherapy.
GSDMD research provides a basis for considering pathogen clearance and host tissue protection together in sepsis. A concrete application scenario would be to measure GSDMD cleavage products alongside existing markers such as lactate in future clinical trials, then explore which immune states and intervention times are associated with benefit from inhibition. Such trials would need to assess organ function, survival, bacterial clearance, and secondary infections as well as reductions in inflammatory markers. Measurement methods must first be standardized and validated in patient cohorts; current evidence does not support recommending treatment based on GSDMD concentrations. The review outlines questions that must be resolved when testing preclinical promise in people.