Daily Sepsis Research Analysis
Three standout studies advance sepsis science and care: a mechanistic Nature study links phospholipid-driven HIF-1α to cytopathic hypoxia in septic cardiomyopathy; a cluster-randomized trial shows a neonatal early-onset sepsis calculator safely cuts antibiotic starts; and organoid work identifies a USP18–STING1 axis driving ferroptosis in sepsis-associated AKI, suggesting new targets.
Summary
Three standout studies advance sepsis science and care: a mechanistic Nature study links phospholipid-driven HIF-1α to cytopathic hypoxia in septic cardiomyopathy; a cluster-randomized trial shows a neonatal early-onset sepsis calculator safely cuts antibiotic starts; and organoid work identifies a USP18–STING1 axis driving ferroptosis in sepsis-associated AKI, suggesting new targets.
Research Themes
- Cytopathic hypoxia mechanisms in septic cardiomyopathy
- Antibiotic stewardship via early-onset sepsis risk stratification
- Ferroptosis pathways in sepsis-associated acute kidney injury
Selected Articles
1. Excessive HIF-1α driven by phospholipid metabolism causes septic cardiomyopathy through cytopathic hypoxia.
This mechanistic study shows that LPS enhances phospholipid metabolism to drive excessive cardiomyocyte HIF-1α, which suppresses mitochondrial respiration via iNOS/NO and causes cytopathic hypoxia, leading to septic cardiomyopathy. Cardiac HIF-1α haploinsufficiency and inhibition of COX2/sPLA2 attenuated mitochondrial and contractile dysfunction, implicating prostaglandins and lysophospholipids via PKA in stabilizing HIF-1α.
Impact: It uncovers a coherent molecular pathway linking inflammatory lipid signaling to HIF-1α-driven cytopathic hypoxia in septic cardiomyopathy, identifying multiple actionable nodes (COX2, sPLA2, PKA, HIF-1α).
Clinical Implications: While preclinical, the work supports testing COX2/sPLA2/PKA modulation or HIF-1α/iNOS attenuation strategies to prevent or treat septic cardiomyopathy, and motivates biomarker development around lipid mediators and HIF-1α activity.
Key Findings
- LPS upregulates cardiomyocyte HIF-1α, suppressing mitochondrial respiration via iNOS-dependent nitric oxide and causing cytopathic hypoxia.
- Cardiac-specific HIF-1α haploinsufficiency ameliorates mitochondrial and contractile dysfunction in a mouse model of septic cardiomyopathy.
- NF-κB–driven COX2 and sPLA2 upregulation increases HIF-1α; their inhibition prevents HIF-1α induction, cytopathic hypoxia, and dysfunction.
- Phospholipid metabolites (prostaglandins, lysophospholipids/free fatty acids) stabilize HIF-1α via PKA activation.
Methodological Strengths
- Multi-tier mechanistic validation including genetic (cardiac HIF-1α deletion) and pharmacologic inhibition (COX2/sPLA2) in vivo.
- Clear causal chain from NF-κB–lipid enzymes to HIF-1α stabilization and mitochondrial dysfunction.
Limitations
- Mouse LPS model may not capture full heterogeneity of human septic cardiomyopathy.
- Lack of validation in human cardiac tissue or clinical cohorts.
Future Directions: Evaluate COX2/sPLA2/PKA or HIF-1α/iNOS modulation in clinically relevant sepsis models and explore translational biomarkers and early-phase trials in septic patients with myocardial dysfunction.
2. Safety and effectiveness of the early-onset sepsis calculator to reduce antibiotic exposure in at-risk newborns: a cluster-randomised controlled trial.
In a 10-hospital cluster RCT (n=1830), using the neonatal EOS calculator halved predefined harm criteria (RR 0.48) and reduced antibiotic starts within 24 hours (7.2% vs 26.6%) compared with categorical guidelines, with similar adverse events and negative cultures on rare readmissions. Median antibiotic duration was longer among those treated in the calculator arm.
Impact: This is the first randomized comparison demonstrating safety and substantial antibiotic reduction with the EOS calculator, directly informing neonatal sepsis risk management and stewardship.
Clinical Implications: Hospitals can implement the EOS calculator to safely reduce empiric antibiotic starts in at-risk newborns, with ongoing attention to treatment duration and local adaptation.
Key Findings
- Predefined harm criteria occurred in 7.0% (calculator) vs 14.6% (categorical); RR 0.48 (95% CI 0.36–0.63).
- Antibiotic initiation within 24 h was 7.2% vs 26.6% (absolute risk reduction 19.0%).
- Median antibiotic duration among treated newborns was longer in the calculator arm (5.5 vs 2.1 days).
- Adverse events were similar; readmissions for suspected EOS were rare and cultures remained negative.
Methodological Strengths
- Cluster-randomized design across 10 hospitals with prespecified co-primary outcomes and ITT/per-protocol analyses.
- Prospective registration (NCT05274776) and real-world implementation of a multivariate risk tool.
Limitations
- Open-label cluster design with potential cluster-level confounding and limited blinding.
- Longer antibiotic duration among treated infants in the calculator arm; generalizability beyond the Dutch-adapted tool requires evaluation.
Future Directions: Refine protocols to reduce treatment duration when antibiotics are indicated, validate in diverse health systems, and integrate with electronic health records for decision support.
3. USP18 promotes ferroptosis in lipopolysaccharide-induced human kidney organoids by stabilizing STING1.
Using LPS-stimulated human kidney organoids, the authors identify USP18 as an LPS-inducible deubiquitinase that binds and stabilizes STING1, thereby promoting ferroptosis. USP18 depletion reduces ferroptosis, while STING1 overexpression rescues it, positioning the USP18–STING1 axis as a potential therapeutic target in SI-AKI.
Impact: It reveals a previously unrecognized ubiquitin-dependent control of ferroptosis in human kidney organoids relevant to sepsis, providing a tractable axis (USP18–STING1) for intervention.
Clinical Implications: Targeting USP18 or STING1 to modulate ferroptosis could complement supportive care in SI-AKI; findings justify drug discovery screening for deubiquitinase or STING modulators.
Key Findings
- USP18 is the only USP upregulated by LPS in human kidney organoids by RNA-seq profiling.
- USP18 depletion significantly reduces ferroptosis in LPS-induced organoids.
- USP18 binds STING1, deubiquitinates it, and prevents proteasomal degradation, stabilizing STING1.
- STING1 overexpression in USP18-deficient organoids rescues and exacerbates ferroptosis.
Methodological Strengths
- Human kidney organoid model with transcriptomics and genetic perturbation for mechanistic mapping.
- Direct protein–protein interaction and deubiquitination evidence linking USP18 to STING1 stability.
Limitations
- Organoid LPS model may not reflect full complexity of human SI-AKI and immune milieu.
- Lack of in vivo validation and pharmacologic inhibitor testing limits translation.
Future Directions: Validate the USP18–STING1 axis in animal SI-AKI models and patient samples; screen for selective USP18 inhibitors or STING modulators to test ferroptosis control and renal outcomes.