Gasdermin D drives the systemic storm and mortality after trauma with hemorrhage to a greater degree in biological females than males

Severe injury accompanied by hemorrhagic shock triggers an early release of cell constituents into the circulation, referred to as the systemic storm. The systemic storm drives the systemic inflammatory response and is associated with increased mortality. The role of programmed cell death (PCD) in the systemic storm was investigated in mice that underwent hemorrhagic shock with tissue trauma (HS/T) followed by crystalloid resuscitation. Wild-type (WT) mice were treated with inhibitors, including z-VAD, necrostatin-1, ferrostatin-1, or disulfiram (DSF), to block the different forms of PCD. Gasdermin D (GSDMD)-dependent PCD was further targeted using <i>Gsdmd</i>^-/- mice. Untargeted metabolomics and proteomics were used as the primary end point to gain a comprehensive view of the composition changes in the circulation. Although all inhibitor strategies partially reversed the systemic storm, the largest reversal occurred in <i>Gsdmd^-/-</i> mice and WT mice treated with DSF, a nonspecific inhibitor of GSDMD pore formation. Weighted correlation network analysis and machine learning identified a subset of omics features increased in the circulation in a GSDMD-dependent manner. Linear regression analysis using a GSDMD-specific omics score (GSOS) in a published multiomic dataset from patients with trauma showed correlation of the GSOS with outcomes and inflammation. Female sex emerged as the variable with the strongest relationship to the GSOS in injured humans, a finding confirmed in mice. Last, DSF treatment or GSDMD deletion led to improvement in blood pressure recovery and increased survival in both sexes. These protective effects of DSF were observed when administered after HS/T, underscoring its potential as a therapeutic intervention.