Daily Sepsis Research Analysis
Two mechanistic studies illuminate how immune-epithelial crosstalk and epigenetic regulation drive organ injury in sepsis, identifying druggable targets in ferroptosis (GBP2–OTUD5–GPX4) and pyroptosis (EZH2–H3K27me3–Nrf2). A nationwide claims-based analysis quantifies COVID-19-associated candidemia (0.3–1.1%) and links it to mortality, highlighting modifiable risk factors.
Summary
Two mechanistic studies illuminate how immune-epithelial crosstalk and epigenetic regulation drive organ injury in sepsis, identifying druggable targets in ferroptosis (GBP2–OTUD5–GPX4) and pyroptosis (EZH2–H3K27me3–Nrf2). A nationwide claims-based analysis quantifies COVID-19-associated candidemia (0.3–1.1%) and links it to mortality, highlighting modifiable risk factors.
Research Themes
- Macrophage extracellular vesicles drive endothelial ferroptosis in sepsis-induced lung injury
- Epigenetic repression of Nrf2 by EZH2 promotes cardiomyocyte pyroptosis in inflammatory injury
- COVID-19-associated candidemia: incidence, risk factors, and mortality impact
Selected Articles
1. Extracellular vesicle-packaged GBP2 from macrophages aggravates sepsis-induced acute lung injury by promoting ferroptosis in pulmonary vascular endothelial cells.
Macrophage EVs carrying GBP2 trigger endothelial ferroptosis via direct binding to OTUD5 and promotion of GPX4 ubiquitination, disrupting the vascular barrier in sepsis-induced lung injury. Plantainoside D binds GBP2, disrupts the GBP2–OTUD5 interaction, reduces GPX4 ubiquitination, and mitigates lung injury in preclinical models.
Impact: Identifies a previously unrecognized EV-mediated GBP2–OTUD5–GPX4 axis that drives endothelial ferroptosis in sepsis, with a small molecule that pharmacologically targets the pathway.
Clinical Implications: Suggests GBP2 or the OTUD5–GPX4 ubiquitination checkpoint as therapeutic targets for sepsis-induced lung injury; EV-GBP2 may serve as a biomarker of endothelial injury. Translation requires safety/pharmacokinetic studies and early-phase clinical trials.
Key Findings
- Macrophage-derived EVs induce endothelial ferroptosis and barrier disruption in sepsis models.
- GBP2 is enriched in EVs and binds OTUD5 to promote GPX4 ubiquitination, driving ferroptosis.
- Plantainoside D binds GBP2, disrupts GBP2–OTUD5 interaction, reduces GPX4 ubiquitination, and attenuates lung injury.
Methodological Strengths
- Multi-system validation (patient samples, cell lines, CLP mice, endothelial-specific Gpx4 knockout)
- Mechanistic dissection with RNAi, AAV, proteomics, docking/MD simulations, and CETSA
Limitations
- Preclinical only; no interventional human data to establish clinical efficacy
- EV-GBP2 quantitation and small-molecule PD require pharmacokinetic/toxicity profiling and off-target assessment
Future Directions: Validate EV-GBP2 as a biomarker in prospective sepsis cohorts and advance GBP2-targeting agents (e.g., PD) through pharmacology and early-phase clinical testing.
Macrophages play a critical role in the development of sepsis-induced acute lung injury (si-ALI), with extracellular vesicles (EVs) acting as crucial mediators. However, the effects and mechanisms of macrophage-derived EVs on si-ALI remain unclear. This study demonstrated that macrophage-derived EVs induce endothelial ferroptosis and barrier disruption during sepsis. Through proteomic sequencing and reanalysis of transcriptomic and single-cell sequencing data, guanylate-binding protein 2 (GBP2) was identified as a key EV molecule. Elevated GBP2 expression was observed in EVs and monocytes from the peripheral blood of sepsis patients, in LPS-stimulated THP-1 and RAW264.7 cells and their secreted EVs, and in macrophages within the lungs of CLP mice. Additionally, GBP2 expression in EVs showed a positive correlation with vascular barrier injury biomarkers, including ANGPT2, Syndecan-1, and sTM. Modulating GBP2 levels in macrophage-derived EVs affected EV-induced ferroptosis in endothelial cells. The mechanism by which GBP2 binds directly to OTUD5 and promotes GPX4 ubiquitination was elucidated using RNA interference, adeno-associated virus transfection, and endothelial-specific Gpx4 knockout mice. A high-throughput screening of small-molecule compounds targeting GBP2 was conducted. Molecular docking, molecular dynamics simulations, and cellular thermal shift assays further confirmed that Plantainoside D (PD) has a potent binding affinity for GBP2. PD treatment inhibited the interaction between GBP2 and OTUD5, leading to a reduction in GPX4 ubiquitination. Further research revealed that PD treatment enhanced the pulmonary protective effects of GBP2 inhibition. In conclusion, this study explored the role of EV-mediated signaling between macrophages and pulmonary vascular endothelial cells in si-ALI, highlighting the GBP2-OTUD5-GPX4 axis as a driver of endothelial ferroptosis and lung injury. Targeting this signaling axis presents a potential therapeutic strategy for si-ALI.
2. EZH2-induced histone methylation in the Nrf2 promoter region mediates pyroptosis in inflammatory cardiomyocyte injury.
In LPS-stimulated cardiomyocytes, EZH2 increases H3K27me3 at the Nrf2 promoter, suppresses Nrf2 transcription, and drives pyroptosis. Genetic modulation shows EZH2 overexpression exacerbates, while EZH2 knockdown and Nrf2 overexpression attenuate, pyroptosis signatures.
Impact: Reveals an epigenetic checkpoint (EZH2–H3K27me3) controlling Nrf2 and pyroptosis in septic myocardial injury, nominating EZH2/Nrf2 as therapeutic targets.
Clinical Implications: Supports exploration of EZH2 inhibitors or Nrf2 activators to mitigate septic cardiomyopathy; requires validation in animal models and human tissues.
Key Findings
- LPS increases EZH2 and decreases Nrf2, triggering cardiomyocyte pyroptosis.
- EZH2 overexpression enhances Caspase-1 activity, N-GSDMD/NLRP3 expression, and IL-1β/IL-18 release.
- ChIP-qPCR shows EZH2 mediates Nrf2 repression via H3K27me3; EZH2 knockdown reduces, and Nrf2 knockdown restores, pyroptosis.
Methodological Strengths
- Mechanistic linkage supported by ChIP-qPCR and multiple pyroptosis readouts
- Gain- and loss-of-function experiments to establish causality (EZH2/Nrf2)
Limitations
- Single-cell line in vitro model without in vivo validation
- LPS-stimulated H9C2 model may not fully recapitulate septic cardiomyopathy complexity
Future Directions: Validate EZH2–Nrf2 regulation in animal models of sepsis and assess pharmacologic EZH2 inhibition/Nrf2 activation for cardiac protection.
Myocardial dysfunction is one of the most severe sepsis syndromes. EZH2 participates in regulating the inflammatory response in tissues; however, its role in septic myocarditis remains unclear. In this study, various concentrations of lipopolysaccharide (LPS) were used to treat H9C2 cells in order to mimic sepsis. Cell pyroptosis was detected by flow cytometry, and further confirmed by the expression of biomarkers and levels of cytokines. Caspase-1 activity was evaluated by flow cytometry and immunofluorescence assays. Gene expression was detected by reverse transcription-PCR (RT-PCR) and western blotting. Chromatin Immunoprecipitation - Quantitative PCR was used to detect the levels of histone methylation in the Nrf2 promoter region. Our results showed that LPS activated cell pyroptosis, promoted EZH2 expression, and inhibited Nrf2 expression in H9C2 cells. Overexpression of EZH2 enhanced LPS-induced cell pyroptosis, as shown by increased Caspase-1 activity, increased expression of N-GSDMD and NLRP3 proteins, and higher levels of IL-1β, IL-18, and LDH. Moreover, overexpression of EZH2 inhibited Nrf2 transcription. In contrast, knockdown of EZH2 suppressed pyroptosis and promoted Nrf2 expression in LPS-treated H9C2 cells. Results of chromatin immunoprecipitation - quantitative PCR verified that EZH2 regulated Nrf2 transcription via H3K27me3 modification. Furthermore, overexpression of Nrf2 inhibited cell pyroptosis and knockdown of Nrf2 promoted cell pyroptosis. Knockdown of Nrf2 reversed the cardioprotective effect of EZH2 knockdown. Collectively, our results suggest that EZH2 promotes cell pyroptosis by enhancing H3K27me3 expression and inhibiting Nrf2 transcription in cardiomyocytes under inflammatory conditions.
3. Assessment of incidence and risk factors of COVID-19-associated candidemia using diagnosis procedure combination data.
Using nationwide DPC claims data from Japan, candidemia occurred in 0.3–1.1% of severe/critical COVID-19 patients and independently increased mortality. Risk factors included renal impairment, steroid use, blood transfusion, and central venous catheter use.
Impact: Quantifies the burden of COVID-19-associated candidemia and identifies modifiable risk factors linked to mortality, informing ICU antifungal stewardship and device management.
Clinical Implications: For severe/critical COVID-19, monitor high-risk patients for candidemia, optimize central line care, reassess steroid exposure, and consider early blood cultures and timely antifungal therapy when indicated.
Key Findings
- Candidemia incidence in severe/critical COVID-19 was 0.3–1.1% in nationwide claims data.
- Renal impairment, steroid use, blood transfusion, and central venous catheter use were risk factors for candidemia.
- Candidemia was an independent risk factor for mortality among severe/critical COVID-19 patients.
Methodological Strengths
- Large-scale, multi-institutional administrative dataset with multivariable adjustment
- Focus on severe/critical cohort with clinically relevant outcomes (mortality)
Limitations
- Claims-based definitions risk misclassification and lack microbiologic granularity (e.g., species, antifungal susceptibility)
- Residual confounding and missing data on antifungal timing/dosing are possible
Future Directions: Link claims to microbiology/pharmacy data to refine risk models and evaluate antifungal stewardship interventions in high-risk COVID-19 patients.
BACKGROUND: Candidemia is an important coronavirus disease 2019 (COVID-19)-associated invasive fungal infection. Patients with COVID-19 may be susceptible to candidemia; however, evidence regarding its incidence, risk factors, and involvement in mortality is insufficient. OBJECTIVES: To explore the incidence of and potential risk factors for candidemia in patients with severe or critical COVID-19 and evaluate the relationship between candidemia and mortality in patients with severe or critical COVID-19. METHODS: The incidence of candidemia in patients with severe and critical COVID-19 was evaluated using administrative claims data from acute care hospitals in Japan. Multivariable regression models were used to explore potential risk factors for candidemia and their contribution to mortality in patients with severe and critical COVID-19. RESULTS: Candidemia occurred in 0.3-1.1 % of patients with severe or critical COVID-19. Renal impairment, use of steroid, blood transfusion, and use of central venous catheter were potential risk factors for candidemia in patients with severe to critical COVID-19. CONCLUSIONS: Candidemia in patients with COVID-19 was an independent risk factor for mortality. Candidemia in patients with severe to critical COVID-19 is a grave complication and may increase mortality.