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.
Septic cardiomyopathy, one manifestation of multiple organ dysfunction syndrome, is a challenging complication in sepsis, and cytopathic hypoxia has been proposed to have a key role in the pathophysiology of multiple organ dysfunction syndrome. However, the underlying mechanisms remain unknown. Here, we show that upregulation of hypoxia-inducible factor-1α (HIF-1α) in cardiomyocytes following lipopolysaccharide (LPS) treatment suppresses mitochondrial respiration via inducible nitric oxide synthase-dependent nitric oxide, leading to cytopathic hypoxia. Cardiac-specific heterozygous deletion of HIF-1α ameliorates mitochondrial and contractile dysfunction in a mouse model of septic cardiomyopathy. Mechanistically, nuclear factor-κB (NF-κB)-mediated upregulation of cyclooxygenase 2 (COX2) and secretory phospholipases A2 (sPLA2) enhances HIF-1α expression following LPS exposure, whereas their inhibition prevents LPS-induced HIF-1α upregulation, cytopathic hypoxia and contractile dysfunction. In addition, phospholipid metabolites (prostaglandins and lysophospholipids/free fatty acids, respectively) stabilize HIF-1α via protein kinase A activation. These findings highlight a crucial role of excessive HIF-1α, driven by LPS-enhanced phospholipid metabolism, in septic cardiomyopathy through induction of cytopathic hypoxia.
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.
BACKGROUND: Newborns are at risk for early-onset sepsis (EOS), occurring 0.2-2.0 per 1000 live births, and for antibiotic overtreatment: approximately 5-15% receive antibiotics for suspected EOS under conventional guidelines with categorical risk factor assessment. Use of the multivariate neonatal EOS calculator prediction tool can reduce overtreatment, but no trials have been conducted to compare its safety to these categorical guidelines. METHODS: Between April 12th, 2022, and March 19th, 2024, we conducted an open-label, two-armed, cluster-randomised controlled trial among newborns born at ≥34 weeks' gestational age with ≥1 EOS risk factor, comparing 10 hospitals randomised 1:1 to EOS calculator use versus categorical guideline use (ClinicalTrials.gov number: NCT05274776). The EOS calculator was slightly adapted for Dutch use. The co-primary non-inferiority outcome assessed safety using four predefined harm criteria (respiratory support, circulatory support, referral to intensive care unit, and culture-confirmed EOS). Non-inferiority was established if the upper limit of the 95% confidence interval (CI) for the relative risk did not exceed 1.5. The co-primary superiority outcome assessed the reduction of participants starting antibiotic therapy for suspected EOS within 24 h postpartum. Secondary endpoints were the duration of antibiotic therapy and the initiation of antibiotic therapy between 24 and 72 h after birth. Intention-to-treat and per-protocol analyses were performed. FINDINGS: 1830 newborns (183 per cluster) were included. At least one harm criterion was present in 64 (7.0%) of 915 in the EOS calculator arm and 134 (14.6%) of 915 in the categorical guideline arm (relative risk 0.48; 95% Cl 0.36-0.63). Antibiotics for suspected EOS were started in 66 (7.2%) of 915 in the EOS calculator arm, compared with 243 (26.6%) of 915 in the categorical guideline arm (absolute risk reduction: 19.0%, 95% CI 11.3-26.7). Median duration of antibiotics was longer in the EOS calculator arm (5.5 days, IQR 1.8-6.6) than in the categorical guideline arm (2.1 days, IQR 1.6-6.3) (P 0.0019). We found no difference in the proportion of newborns started on antibiotic therapy for suspected EOS between 24 and 72 h after birth. Adverse event rates were similar between arms. Readmission for suspected early-onset sepsis occurred three times in the EOS calculator and two times in the categorical guideline arm. Any cultures obtained at readmission remained negative, and any symptoms resolved completely. INTERPRETATION: These trial data support safety and effectiveness of the EOS calculator for harm criteria and for the proportion of participants that started antibiotic therapy. FUNDING: This study was supported by SPIN, the General Paediatrics Research Network of the Dutch Association for Paediatrics, supported by het Cultuurfonds.
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.
Sepsis-induced acute kidney injury (SI-AKI) is a severe condition with limited therapeutic options, resulting in poor prognosis. Ferroptosis exacerbates the damage caused by SI-AKI, but the mechanisms regulating ferroptosis, especially those involving ubiquitination regulators, remain poorly understood. Here, we used a lipopolysaccharide (LPS)-induced human kidney organoid (HKO) model to investigate ferroptosis in SI-AKI. RNA sequencing (RNA-seq) analysis of control and LPS-treated HKOs revealed USP18 as the only upregulated ubiquitin-specific protease (USP) in response to LPS. Further investigations showed that depletion of USP18 significantly reduced ferroptosis in LPS-induced HKOs. To explore the mechanism underlying USP18's pro-ferroptotic role, we screened four ferroptosis-related drivers and identified STING1 as the key interacting protein with USP18. Mechanistically, USP18 directly binds to STING1, deubiquitinates it, and prevents its proteasomal degradation in HKOs. Overexpression of STING1 in USP18-deficient HKOs exacerbated ferroptosis, indicating that STING1 is crucial for mediating USP18's ferroptosis-promoting function in LPS-induced HKOs. Together, these findings establish that USP18-STING1 axis plays role in LPS-induced ferroptosis in HKOs, illuminating that targeting USP18-STING1 could provide neoteric therapeutic approach for treating SI-AKI.