Daily Sepsis Research Analysis
Analyzed 34 papers and selected 3 impactful papers.
Summary
Analyzed 34 papers and selected 3 impactful articles.
Selected Articles
1. In vivo chemogenetic RNA editing of macrophages by bioengineered viruses for sepsis treatment.
The authors develop a chemogenetically controllable CasRx RNA-editing platform delivered by biomineralized lentiviruses to M1 macrophages. A small-molecule ligand repeatedly activates editing to downregulate NLRP3 and attenuate inflammation, demonstrating efficacy in mouse sepsis models.
Impact: Introduces a controllable, host-directed RNA-editing therapy targeting macrophages, enabling on-demand and repeatable immunomodulation in sepsis.
Clinical Implications: While preclinical, this platform suggests a pathway to precision immunotherapy in sepsis by transiently silencing inflammasome drivers (e.g., NLRP3). Clinical translation will require rigorous evaluation of vector safety, biodistribution, off-target editing, and immunogenicity.
Key Findings
- Engineered biomineralized lentiviral vectors delivered CasRx RNA-editing machinery and chemogenetic switches selectively to M1 macrophages in vivo.
- A small-molecule ligand activated the chemogenetic switch to repeatedly downregulate NLRP3 mRNA, enabling on-demand control of inflammatory signaling.
- In murine sepsis models, chemogenetic CasRx editing mitigated inflammatory responses and was effective upon repeated activations.
Methodological Strengths
- Targeted in vivo delivery with chemogenetic on–off control enabling temporal precision
- Demonstrated efficacy and repeatability across murine sepsis models
Limitations
- Preclinical animal study; human safety and efficacy remain untested
- Potential vector-related immunogenicity and off-target RNA editing require evaluation
Future Directions: Optimize targeting and dosing, map off-target edits and biodistribution, assess durability and safety in large-animal models, and design early-phase clinical trials possibly as adjuncts to antimicrobials.
2. Aromatic microbial metabolite hippuric acid enhances inflammatory responses in macrophages via TLR-MyD88 signaling and lipid remodeling.
Hippuric acid, a microbiome-derived metabolite, selectively amplifies MyD88-dependent TLR signaling in M1-like macrophages, driven by cholesterol biosynthesis–linked lipid remodeling. It worsens survival in infected mice and correlates with mortality in sepsis, suggesting a biomarker and therapeutic target.
Impact: Defines a mechanistic link between a specific microbiome metabolite, TLR-MyD88 signaling, and lipid remodeling with translational relevance to human sepsis outcomes.
Clinical Implications: Hippuric acid may serve as a prognostic biomarker and points to MyD88 signaling and cholesterol biosynthesis as druggable nodes. Nutritional or microbiome-targeted strategies could be explored to modulate hippuric acid levels or downstream pathways.
Key Findings
- Hippuric acid enhanced pro-inflammatory responses in M1-like macrophages via MyD88-dependent TLRs but not via TRIF, STING, or NOD2 pathways.
- Genetic deletion of MyD88 abolished hippuric acid–induced pro-inflammatory responses.
- Transcriptomic and lipidomic data showed increased cholesterol biosynthesis and lipid accumulation; lowering cellular cholesterol blunted hippuric acid’s effects.
- Hippuric acid increased inflammation and reduced survival in infected mice, enhanced responses in human macrophages, and higher levels correlated with sepsis mortality.
Methodological Strengths
- Integrated multi-omics (transcriptomics and lipidomics) with genetic knockout validation
- Cross-species validation including murine models and human macrophages with clinical correlation
Limitations
- Causality in human sepsis is not established; mortality association is correlative
- Exposure levels and pharmacokinetics of hippuric acid in patients were not interventionally manipulated
Future Directions: Prospective clinical studies to validate hippuric acid as a prognostic biomarker; testing pharmacologic modulation of MyD88 signaling or cholesterol biosynthesis; dietary/microbiome interventions to reduce detrimental metabolite burden.
3. The MafG/Bach1-Lcn2 transcriptional axis drives ferroptosis in Sepsis-induced Acute Lung Injury via disrupting redox homeostasis.
MafG is upregulated in septic lungs and, together with Bach1, drives Lcn2 transcription to promote iron accumulation and lipid peroxidation, culminating in ferroptosis in alveolar epithelium. Genetic knockdown and the candidate inhibitor Anemoside B4 ameliorated lung injury and improved survival in CLP mice.
Impact: Identifies a druggable transcriptional pathway for ferroptosis in sepsis-associated lung injury and provides both genetic and small-molecule evidence of therapeutic modulation.
Clinical Implications: Suggests MafG/Bach1–Lcn2 signaling and ferroptosis as therapeutic targets in SALI; Lcn2 and redox markers could inform patient stratification. Translation requires validation of AB4 specificity, pharmacokinetics, and safety.
Key Findings
- MafG was significantly upregulated in septic lungs and alveolar epithelial cells; overexpression exacerbated ferroptosis, whereas knockdown was protective.
- MafG formed a functional heterodimer with Bach1 that directly activated Lcn2 transcription, promoting iron accumulation and lipid peroxidation.
- Lcn2 overexpression reversed the anti-ferroptotic effect of MafG silencing, confirming pathway causality.
- AAV-mediated MafG knockdown and Anemoside B4 treatment reduced lung injury, improved redox balance, and enhanced survival in CLP mice.
Methodological Strengths
- Comprehensive mechanistic validation (co-IP, luciferase reporter, multi-omics markers) with in vivo CLP models
- Dual therapeutic testing using genetic knockdown and a small-molecule inhibitor
Limitations
- Preclinical murine study; human validation and safety data are lacking
- Specificity and off-target profiles of Anemoside B4 are not fully characterized
Future Directions: Evaluate MafG/Bach1 inhibitors with defined pharmacology, validate biomarkers in human SALI cohorts, and test timing/dosing strategies and combinations with antimicrobial/anti-inflammatory therapies.