ArticleInflammation research : official journal of the European Histamine Research Society ... [et al.]2026
Delayed disulfiram targeting GSDMD-NETs axis rescues sepsis by limiting bacterial spread and lung injury.
Article in Inflammation research : official journal of the European Histamine Research Society ... [et al.], 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- Source-controlled bacterial peritonitis improves survival but leaves persistent lung inflammation and airway IgA loss.Intensive care medicine experimental · 2026Article
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3 authors.
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Abstract
backgroundSepsis therapy faces a critical paradox: Gasdermin D (GSDMD)-mediated neutrophil extracellular traps (NETs) exert protective host defense early but drive tissue injury late. Defining the temporal dynamics of intervening in this axis is central to overcoming therapeutic limitations.
methodsIn a cecal ligation and puncture (CLP) model recapitulating human sepsis progression, disulfiram (DSF, 80 mg/kg) or vehicle was administered intraperitoneally at 0 h, 4 h, or 8 h postoperatively. A comprehensive multidimensional analysis assessed survival, bacterial burden (lung/blood/peritoneum), cytokines (TNF-α/IL-6/IL-1β), lung injury (histopathology/wet-dry ratio/Evans Blue extravasation), GSDMD activation, NET formation (Sytox-green/CitH3-MPO), and neutrophil function (LY6G
resultsImmediate DSF (0 h) proved detrimental, exacerbating bacterial dissemination (lung↑, P = 0.0036; blood↑, P = 0.0488), hyperinflammation (TNF-α↑, P = 0.0165; IL-6↑, P = 0.0140), and shortening survival (P = 0.0417). Conversely, delayed DSF (8 h) yielded significant benefits, reducing bacterial load (lung↓, P = 0.0002; blood↓, P = 0.0309), suppressing cytokines (TNF-α↓, P = 0.0121; IL-6↓, P = 0.0022), and extending survival (P < 0.0001). Mechanistically, while DSF consistently inhibited GSDMD cleavage and NETs, only delayed intervention attenuated NET-driven microthrombosis, reduced LY6G
conclusionTargeting the GSDMD-NETs axis is fundamentally timing-dependent. Immediate inhibition disrupts essential host defenses, whereas delayed treatment (8 h post-CLP) preserves bacterial clearance, reduces lung injury, and improves survival. By establishing a therapeutic window, our study provides the first systematic evidence that the success of disulfiram in sepsis depends on when it is administered, offering a clinically actionable framework to guide future biomarker-driven trials and bedside decision-making in critical care.
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