Shenfu Injection reduces septic lethality by preserving glycocalyx integrity and inhibiting caspase-11-dependent...

Sepsis is a life-threatening condition and a leading cause of in-hospital mortality, characterized by dysregulated inflammatory responses. Using murine models, this study investigated whether Shenfu Injection (SFI), a clinically approved botanical formulation, protects against sepsis by preserving glycocalyx integrity and modulating noncanonical inflammasome signaling mediated by murine caspase-11.

C57BL/6 mice were subjected to cecal ligation and puncture (CLP) or endotoxemia and treated with SFI or saline. Seven-day survival, organ injury, plasma cytokines, and glycocalyx markers were assessed. For mechanistic studies, knockout mice (Caspase-11^⁻/⁻, NLRP3^⁻/⁻, Hpse^⁻/⁻) and primary peritoneal macrophages were used to evaluate cytosolic LPS delivery, caspase-11-LPS interaction, and gasdermin D (GSDMD) cleavage.

SFI treatment significantly improved survival in endotoxemia (15% vs. 54%, P < 0.05) and CLP models (15% vs. 45%, P < 0.05). Treated mice displayed reduced organ injury and lower plasma IL-1α and IL-1β levels. Mechanistically, SFI selectively inhibited caspase-11 activation and GSDMD cleavage, thereby attenuating pyroptosis. Upstream, SFI preserved glycocalyx integrity by preventing heparanase-mediated degradation, which in turn blocked outer membrane vesicle (OMV)-driven cytosolic LPS delivery.

SFI mitigates organ damage and reduces lethality in sepsis by targeting a central pathogenic axis involving glycocalyx degradation, OMV-mediated LPS translocation, and caspase-11-dependent pyroptosis, supporting its potential as an adjunctive therapy for sepsis.