The lethal switch in sepsis, gasdermin D: Inhibition of multi-organ damage through pyroptosis blockade
##1. The hidden destroyer of sepsis, gasdermin D (GSDMD) and pyroptosis Sepsis is a lethal disease that claims 11 million lives worldwide each year, causing profound immune dysregulation. Recent studies have identified gasdermin D (GSDMD), which drives the form of cell death known as pyroptosis, as a central engine of sepsis pathophysiology. GSDMD creates pores in the membranes of immune cells, leading to cell lysis and a potent inflammatory response, acting as a catalyst for systemic injury beyond the initial infection.
##2. Molecular mechanisms of multi-organ failure: caspase axis and plasma membrane pore formation Exposure to danger signals such as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) activates caspase‑1 (canonical pathway) and caspase‑4/5/11 (non‑canonical pathway), which cleave GSDMD. The N‑terminal fragment of cleaved GSDMD inserts into the plasma membrane to form physical pores, leading to cell death. This process exacerbates pneumonia through alveolar macrophage destruction, sustains bacteremia via hepatic HMGB1 release, promotes renal microthrombosis, and precipitates blood‑brain barrier (BBB) disruption, thereby initiating a cascade that results in multi‑organ failure.
##3. Innovative therapeutic strategy: combination of disulfiram and anti‑GSDMD antibody Novel agents that directly target GSDMD are generating clinical enthusiasm. Disulfiram, originally approved for alcohol‑dependence treatment, binds to the Cys191 residue of GSDMD and blocks pore formation, while the specific antibody mAb26.5 demonstrated a remarkable reduction in mortality to 30 % in sepsis models. Moreover, co‑administration of the antibiotic imipenem with disulfiram is expected to provide synergistic benefits by simultaneously eliminating bacteria and protecting host cells.
##4. Dawn of precision medicine: stage‑specific immunotherapy guided by GSDMD concentration The future of sepsis treatment lies in stage‑adapted interventions based on the patient’s immune status. The research team defined a GSDMD‑NT concentration ≥120 ng/mL as a “hyperinflammatory endotype” and proposed a precision strategy of administering intensive GSDMD inhibitors at this stage. This approach moves beyond the conventional blanket use of antibiotics, integrating single‑cell omics data to determine the optimal timing of therapy tailored to each patient’s immune trajectory, heralding a true era of precision sepsis medicine.
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.
This dataset quantifies the complex immune response in sepsis using the quantitative metric of GSDMD concentration, providing therapeutic guidelines. It serves as a critical reference for AI algorithm training to predict sepsis patient prognosis and determine the timing of immunomodulatory agent administration.