Nanocatalytic Inhibition of ROS‐Dependent GSDMD Palmitoylation Mitigates Sepsis Progression

Sepsis is a life-threatening condition characterized by multiple organ dysfunction, high morbidity, and mortality. Gasdermin D (GSDMD)-mediated pyroptosis constitutes a key pathogenic mechanism. Here, we discovered that GSDMD in peripheral blood mononuclear cells (PBMCs) from septic patients undergoes enhanced palmitoylation, driven by reactive oxygen species (ROS) and mediated by ZDHHC5/ZDHHC9 transferases. Targeting this new mechanism, we designed and screened vanadium oxide hydroxide nanosheets (VOOH NSs) as catalytic ROS scavengers and GSDMD palmitoylation inhibitor. Crucially, we investigated and optimized the exposure patterns of specific lattice planes to maximize their ROS-eliminating capability. This intervention measure prevents GSDMD palmitoylation, inhibits both canonical and non-canonical pyroptosis, alleviates inflammatory damage, and demonstrates potent therapeutic effects in two sepsis animal models. Validation in GSDMD-knockout mice further confirms this palmitoylation pathway as the key therapeutic target. These results demonstrate that targeting ROS-mediated GSDMD palmitoylation is a key therapeutic strategy for treating sepsis.