Daily Sepsis Research Analysis
Three high-impact sepsis studies advanced mechanistic understanding and translational therapy. A mechanistic study uncovered an Acod1/itaconate–UBR5–PAD4 axis that suppresses NETosis, a primate trial showed factor XI inhibition (abelacimab) improved survival without bleeding, and a preclinical study identified narciclasine as a dual-action cardioprotective agent via BNIP3-mediated mitophagy and ferroptosis suppression.
Summary
Three high-impact sepsis studies advanced mechanistic understanding and translational therapy. A mechanistic study uncovered an Acod1/itaconate–UBR5–PAD4 axis that suppresses NETosis, a primate trial showed factor XI inhibition (abelacimab) improved survival without bleeding, and a preclinical study identified narciclasine as a dual-action cardioprotective agent via BNIP3-mediated mitophagy and ferroptosis suppression.
Research Themes
- Targeting immunothrombosis/coagulation in sepsis
- Metabolic-ubiquitin regulation of NETosis
- Mitochondrial quality control and ferroptosis in septic cardiomyopathy
Selected Articles
1. Acod1 Promotes PAD4 Ubiquitination via UBR5 Alkylation to Modulate NETosis and Exert Protective Effects in Sepsis.
Using patient samples and CLP mouse models, the study identifies a metabolic-ubiquitin axis wherein Acod1/itaconate alkylates and activates UBR5 to promote K48-linked ubiquitination and degradation of PAD4, thereby suppressing NETosis. Acod1 knockout worsened inflammation, organ injury, and survival, positioning the Acod1–UBR5–PAD4 axis as a therapeutic target in sepsis.
Impact: Reveals a previously unrecognized mechanism linking immunometabolism to NETosis control in sepsis, identifying druggable nodes (UBR5, PAD4).
Clinical Implications: Suggests a strategy to modulate NETosis by boosting Acod1/itaconate signaling or directly targeting UBR5–PAD4 interactions, which could reduce tissue injury in sepsis.
Key Findings
- NET levels were elevated in sepsis patients and CLP mice and correlated with Acod1 expression.
- Acod1 knockout increased NETosis, inflammation, organ injury, and mortality in CLP sepsis.
- Acod1/itaconate alkylated and enhanced UBR5, promoting K48-linked ubiquitination and degradation of PAD4, thereby suppressing NETosis.
Methodological Strengths
- Integrated multi-omics with genetic knockouts and in vivo validation
- Mechanistic mapping using co-immunoprecipitation and functional assays
Limitations
- Preclinical models may not fully recapitulate human sepsis heterogeneity
- Pharmacologic modulations of itaconate/UBR5 require translational dosing and safety data
Future Directions: Evaluate pharmacologic activators/inhibitors of the Acod1–UBR5–PAD4 axis in diverse sepsis models and assess NET-targeted modulation in early-phase clinical studies.
2. Protective effects of factor XI inhibition by abelacimab in a baboon model of live Staphylococcus aureus sepsis.
In a randomized baboon model of live S. aureus sepsis, abelacimab (FXI inhibitor) achieved 100% 7-day survival versus 50% mortality in controls, attenuated coagulopathy without bleeding, and reduced inflammatory and endothelial injury signatures. Proteomics supported modulation of coagulation, inflammation, and tissue injury pathways.
Impact: Provides translational evidence in a nonhuman primate model that targeting FXI can improve survival while avoiding bleeding—directly informing clinical development of anticoagulant strategies in sepsis.
Clinical Implications: Supports evaluating FXI inhibitors (e.g., abelacimab) in early-phase sepsis trials to mitigate immunothrombosis and organ failure with a favorable bleeding profile.
Key Findings
- Abelacimab-treated baboons had 100% 7-day survival; 3/6 controls died within 102 hours.
- FXI inhibition attenuated sepsis-induced coagulopathy without bleeding signs.
- Treatment reduced proinflammatory cytokines, neutrophil activation, and preserved endothelial integrity; proteomics showed broad pathway modulation.
Methodological Strengths
- Randomized nonhuman primate model with clinically relevant live-pathogen sepsis
- Multimodal assessment including coagulation, inflammation, endothelial markers, pathology, and proteomics
Limitations
- Small sample size and single-pathogen model limit generalizability
- Preclinical design; dosing/timing and efficacy across heterogeneous human sepsis remain to be defined
Future Directions: Dose-finding and safety studies of FXI inhibition in early human sepsis, and evaluation across diverse pathogens and comorbidity profiles.
3. Narciclasine mitigates sepsis-induced cardiac dysfunction by enhancing BNIP3-mediated mitophagy and suppressing ferroptosis.
Narciclasine improved short-term survival and cardiac function in LPS and CLP sepsis models by suppressing ferroptosis (restoring GSH, reducing MDA, modulating TFRC/GPX4/HO-1) and enhancing BNIP3-mediated mitophagy (increased PINK1/PARK2 recruitment and LC3-ATP5B colocalization). Genetic BNIP3 loss abrogated benefits, establishing BNIP3 as a key mediator.
Impact: Introduces a dual-mechanism small molecule approach that targets ferroptosis and mitochondrial quality control for septic cardiomyopathy, with strong genetic validation.
Clinical Implications: Positions BNIP3-mediated mitophagy and ferroptosis as therapeutic axes for sepsis-related cardiac injury; narciclasine or analogs warrant pharmacokinetic and safety studies for potential translation.
Key Findings
- Narciclasine improved 72-hour survival and restored LVEF/FS/CO in LPS and CLP sepsis models in a dose-dependent manner.
- Reduced ferroptosis markers (iron overload, MDA) and restored glutathione; modulated TFRC, GPX4, and HO-1 expression.
- Enhanced BNIP3-dependent mitophagy (PINK1/PARK2 recruitment, LC3-ATP5B colocalization); BNIP3 knockdown/silencing abolished benefits.
Methodological Strengths
- Convergent validation across two in vivo models and in vitro cardiomyocytes
- Genetic perturbation (siRNA and AAV9 BNIP3 silencing) confirming mechanism
Limitations
- Predominantly prophylactic dosing; therapeutic window and timing remain to be defined
- Preclinical study; human pharmacology and off-target effects are unknown
Future Directions: Define therapeutic dosing windows, assess combination strategies with standard sepsis care, and evaluate narciclasine analogs with improved pharmacology.