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Objective and design <p>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.</p> Material and subjects <p>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 (<i>Caspase-11</i><sup><i>⁻/⁻</i></sup>, <i>NLRP3</i><sup><i>⁻/⁻</i></sup>, <i>Hpse</i><sup><i>⁻/⁻</i></sup>) and primary peritoneal macrophages were used to evaluate cytosolic LPS delivery, caspase-11–LPS interaction, and gasdermin D (GSDMD) cleavage.</p> Results <p>SFI treatment significantly improved survival in endotoxemia (15% vs. 54%, <i>P</i> &lt; 0.05) and CLP models (15% vs. 45%, <i>P</i> &lt; 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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年4月1日

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  • Chang Zhang,
  • Huan Chen,
  • Zhongtai Wang,
  • Xiangyu Wang,
  • Zhaozheng Li,
  • Fang Liang,
  • Jian Shi,
  • Ben Lu,
  • Yiting Tang

摘要

Objective and design

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.

Material and subjects

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.

Results

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.

Conclusions

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.