Daily ReportSep 15, 2026
Sepsis, September 15 edition
We read 51 papers and selected 3.
Summary
Today’s most impactful sepsis studies span mechanistic immunology, translational therapeutics, and imaging-based prognosis. Notable advances include identification of an HSF1–C5aR1 pathway that strengthens neutrophil antimicrobial defense, demonstration that NMN may suppress ferroptotic liver injury through the cGAS–STING–ACSL4 axis, and external validation of CT-derived body-composition risk stratification.
Research Themes
- Mechanistic regulation of innate immunity and organ injury
- Novel pharmacological strategies targeting ferroptosis and inflammation
- Imaging-based prognostic stratification in sepsis
Selected Articles
1. HSF1 Protects Against Sepsis by Transcriptionally Upregulating Neutrophil C5aR1 to Enhance Antimicrobial Defense.
This translational mechanistic study showed that C5aR1 expression on circulating neutrophils and soluble plasma C5aR1 levels are reduced in patients and mice with sepsis and correlate inversely with disease severity. HSF1 directly binds the C5aR1 promoter and enhances its transcription, while C5aR1 overexpression improves antimicrobial defense, reduces bacterial burden, and limits organ injury in septic mice.
Impact: The study connects a stress-response transcription factor to complement receptor regulation and neutrophil antimicrobial function, providing a coherent molecular pathway with diagnostic and therapeutic implications. Its use of human observations together with in vivo mechanistic validation strengthens translational relevance.
Clinical Implications: C5aR1 expression or soluble C5aR1 may serve as biomarkers of sepsis severity, while pharmacological enhancement of the HSF1–C5aR1 pathway could represent a future strategy to restore neutrophil antimicrobial activity. Clinical translation will require validation of receptor measurements and testing of pathway-directed interventions in human sepsis.
Key Findings
- Neutrophil membrane C5aR1 and plasma soluble C5aR1 were reduced in patients and mice with sepsis and were inversely associated with disease severity.
- HSF1 directly bound the C5aR1 promoter and transcriptionally increased C5aR1 expression.
- C5aR1 overexpression reduced bacterial burden and tissue injury in septic mice, supporting the HSF1–C5aR1 axis as a therapeutic target.
Methodological Strengths
- Integrated human sepsis observations with septic and HSF1-deficient mouse models.
- Used RNA sequencing, electrophoretic mobility shift assays, and dual-luciferase reporter assays to support the transcriptional mechanism.
Limitations
- The therapeutic experiments were performed in mice, and clinical efficacy or safety in humans was not established.
- The abstract does not report the human and animal sample sizes or detailed control of potential clinical confounders.
Future Directions: Prospective studies should determine whether membrane or soluble C5aR1 improves early risk stratification and treatment monitoring. Further work should develop safe HSF1–C5aR1-directed interventions and test them in clinically relevant polymicrobial sepsis models before human trials.
Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. The resulting septic shock and multiple organ dysfunction syndrome (MODS) are the primary drivers of mortality. Heat shock factor 1 (HSF1), a master transcription factor regulating cellular stress responses, has been shown to exert protective effects during sepsis. Here, our RNA-seq analysis revealed a significant downregulation of complement C5a receptor 1 (C5aR1) in both HSF1-deficient and septic mice; however, the precise role of C5aR1 in sepsis progression remains poorly understood.
2. Automated CT-derived visceral-to-subcutaneous fat ratio as a prognostic imaging biomarker for mortality in sepsis.
In 1,716 patients with sepsis, automated CT-derived visceral-to-subcutaneous fat ratio (VSR) was independently associated with mortality after adjustment for clinical variables. A machine-learning survival model incorporating VSR achieved strong discrimination and retained incremental value in both internal and external validation cohorts, with interactions involving lactate and procalcitonin.
Impact: This study moves body-composition assessment toward automated, reproducible risk stratification and includes an external validation cohort, a major requirement for clinical prediction research. The marker could complement conventional severity assessment without requiring an additional imaging procedure when CT is already clinically indicated.
Clinical Implications: Automated VSR measurement could help identify septic patients at higher mortality risk and support individualized monitoring or escalation of care. Before routine use, the segmentation pipeline, threshold values, calibration, and clinical decision pathways should be validated prospectively across different scanners, populations, and healthcare settings.
Key Findings
- The multicenter cohort included 1,716 patients divided into training, internal validation, and external validation cohorts.
- Higher VSR was independently associated with mortality, with a hazard ratio of 2.117 and p<0.001.
- Adding VSR improved the clinical model C-index by 0.049 in training, 0.080 in internal validation, and 0.020 in external validation cohorts.
Methodological Strengths
- Used a relatively large multicenter cohort with independent external validation.
- Applied automated nnU-Net body-composition segmentation and compared five machine-learning survival approaches.
Limitations
- The observational design cannot establish that VSR causes increased mortality or that modifying body composition would improve outcomes.
- The abstract does not specify the source databases, follow-up duration, or whether model calibration and decision thresholds were prospectively assessed.
Future Directions: Prospective multicenter implementation studies should evaluate whether VSR-guided risk stratification changes monitoring, resource allocation, or treatment decisions and improves patient outcomes. Research should also assess robustness across ethnicities, body habitus, CT protocols, and patients without clinically obtained abdominal CT.
OBJECTIVE: To evaluate the prognostic value of automated CT-derived visceral-to-subcutaneous fat ratio (VSR) and its associations with inflammatory and metabolic biomarkers in sepsis. MATERIALS AND METHODS: In this multicenter study, 1716 patients with sepsis were assigned to training (n = 905), internal validation (n = 388), and external validation (n = 423) cohorts. Body composition was segmented using nnU-Net. Five machine learning-based survival models were developed: gradient boosting survival, fast kernel survival support vector machine, extra survival trees (EST), random survival forest, and Cox proportional hazards survival model.
3. NMN Mitigates LPS-Induced Liver Injury by Inhibiting Ferroptosis via Suppression of the cGAS-STING-ACSL4 Axis.
Using LPS-induced liver injury models and primary-cell systems, the study demonstrated that inflammatory signals from macrophages aggravate hepatocyte ferroptosis. NMN suppressed mitochondrial DNA-mediated cGAS–STING activation and destabilized the STING–ACSL4 complex, thereby simultaneously reducing inflammation and ferroptosis.
Impact: The paper identifies a previously underdefined link between innate immune signaling and ferroptosis in septic liver injury and proposes NMN as a pharmacologically accessible intervention. The molecular interaction between STING and ACSL4 provides a concrete target for future drug development.
Clinical Implications: NMN or therapies targeting the cGAS–STING–ACSL4 pathway could eventually be evaluated as adjunctive treatments for sepsis-associated liver injury. However, the evidence currently supports only preclinical development because the models used were LPS-based and no human efficacy data were provided.
Key Findings
- LPS induced inflammation and ferroptosis in macrophages and hepatocytes, with macrophage-derived paracrine signals worsening hepatocyte injury.
- NMN suppressed mitochondrial DNA-mediated cGAS–STING activation and reduced inflammatory and ferroptotic responses.
- Molecular and biochemical assays showed that NMN weakened the STING–ACSL4 interaction, identifying this complex as a potential therapeutic target.
Methodological Strengths
- Combined in vivo liver injury models with primary hepatocyte, primary macrophage, and THP-1 cell systems.
- Used complementary approaches including domain mapping, molecular simulation, surface plasmon resonance, co-immunoprecipitation, and proximity ligation assays.
Limitations
- The principal in vivo model was LPS-induced injury, which may not reproduce the pathogen complexity and immune dynamics of polymicrobial sepsis.
- The study provides no human pharmacokinetic, safety, or clinical efficacy data for NMN.
Future Directions: Future studies should test NMN in clinically relevant polymicrobial sepsis models, define dose–response and treatment windows, and evaluate interactions with antibiotics and organ-support therapies. Biomarker-guided studies should determine whether cGAS–STING or ferroptosis signatures identify patients most likely to benefit.
Sepsis often leads to severe liver damage, and currently few effective therapies are available for it. Nicotinamide mononucleotide (NMN), a well-known anti-aging agent, exerts organ-protective effects, yet its detailed mechanisms against acute liver injury remain poorly understood. Here, we established LPS-induced liver injury mouse models, along with in vitro models using primary hepatocytes, primary macrophages and THP-1 cells. We found that LPS triggers ferroptosis and inflammation in both macrophages and hepatocytes, and paracrine inflammatory signals from macrophages further aggravate hepatocyte ferroptosis.