Daily Sepsis Research Analysis
Three impactful sepsis studies span mechanisms, stewardship, and therapeutics. A Circulation Research paper uncovers lactate-driven HADHA lactylation as a causal mechanism for sepsis-induced myocardial depression. A 20-year interrupted time-series shows carbapenem preauthorization sustainably reduces use without worsening mortality and correlates with lower resistance, while a preclinical study demonstrates Salvianolic acid A directly targets STING to blunt inflammation and improve survival in a
Summary
Three impactful sepsis studies span mechanisms, stewardship, and therapeutics. A Circulation Research paper uncovers lactate-driven HADHA lactylation as a causal mechanism for sepsis-induced myocardial depression. A 20-year interrupted time-series shows carbapenem preauthorization sustainably reduces use without worsening mortality and correlates with lower resistance, while a preclinical study demonstrates Salvianolic acid A directly targets STING to blunt inflammation and improve survival in a CLP sepsis model.
Research Themes
- Mechanisms of sepsis-induced organ dysfunction
- Antimicrobial stewardship and resistance mitigation
- Targeted immunomodulation in sepsis
Selected Articles
1. Lactylation of HADHA Promotes Sepsis-Induced Myocardial Depression.
Using LPS and CLP sepsis models plus in vitro systems, the authors identify lactate-driven lactylation of HADHA at K166 and K728 as a causal mechanism impairing mitochondrial function and cardiomyocyte contractility. SIRT1 and SIRT3 regulate these modifications, positioning lactylation as a therapeutic target for septic cardiomyopathy.
Impact: This is a rigorous mechanistic discovery linking lactate signaling to a specific posttranslational modification that drives septic myocardial depression, opening a tractable axis (HADHA lactylation/SIRT1/3) for intervention.
Clinical Implications: Although preclinical, these findings suggest measuring or modulating cardiac lactylation and targeting SIRT1/3 or HADHA-lactylation could mitigate septic cardiomyopathy. They also reframe lactate as an active modifier, not just a biomarker.
Key Findings
- Identified lactylation at HADHA K166 and K728 in septic myocardium and LPS-treated cells; levels were lactate dependent.
- HADHA lactylation inhibited enzymatic activity, impaired mitochondrial function and ATP production, reducing cardiomyocyte contractility in vitro and in vivo.
- SIRT1 and SIRT3 regulated HADHA lactylation; 1127 lysine lactylation sites were mapped with 83 differentially lactylated in sepsis.
Methodological Strengths
- Integrated proteomics, transcriptomics, and metabolomics with in vivo (CLP/LPS) and in vitro validation.
- Site-directed mutagenesis of HADHA and functional assays linking modification to mitochondrial and contractile phenotypes.
Limitations
- Preclinical rodent and cell models; human validation of HADHA lactylation and therapeutic modulation is lacking.
- Use of H9c2 cell line may not fully recapitulate adult human cardiomyocyte biology.
Future Directions: Validate HADHA lactylation in human septic cardiomyopathy, test pharmacologic modulation (e.g., SIRT1/3 activators/inhibitors) and develop assays to monitor cardiac lactylation in patients.
BACKGROUND: Serum lactate levels are used to evaluate tissue hypoxia and predict outcomes in cases of sepsis and septic shock. Lactate can participate in a posttranslational modification known as lactylation. Myocardial depression during sepsis and septic shock is common. Here, we investigated the role of lactate in sepsis-induced myocardial depression. METHODS: Septic myocardial depression in rats was induced by lipopolysaccharide administration or cecal ligation and puncture. Lactylation and protein profiles of heart tissues from the control and lipopolysaccharide groups were analyzed using proteomic analysis. Lactylation of the HADHA (trifunctional enzyme subunit alpha) at K166 and K728 was detected in septic heart tissues and lipopolysaccharide-induced cultured cells. Mutation of K166 and K728 HADHA were used to clarify the effects of HADHA lactylation on mitochondrial function, ATP production, energy metabolism, and heart function. Transcriptomic and metabolomic analyses were used to identify differentially expressed genes and differential metabolites in H9c2 (rat cardiomyoblast cell line) cells. RESULTS: We identified 1127 lysine lactylation sites, with 83 differentially lactylated lysine sites. By integrating multifeature hybrid learning and protein language models, we identified lactylation at K166 and K728 of the HADHA as functionally important. We confirmed that lactylation at these sites was influenced by lactate levels and inhibited the HADHA activity, which disturbed mitochondrial function, ATP production, and energy metabolism. This reduction in the contraction force of cardiomyocytes can influence heart function in vitro and in vivo. Furthermore, this study revealed that sirtuin 1 and sirtuin 3 regulated the lactylation of HADHA at K166 and K728. CONCLUSIONS: This study reveals the significant impact of lactylation on cardiomyocyte metabolism. Lactate-induced HADHA lactylation disturbs cardiomyocyte mitochondrial function and metabolism and promotes sepsis-induced cardiac dysfunction. These findings inform the development of new therapeutic targets for sepsis-induced myocardial depression.
2. Long-term effect of carbapenem preauthorization: an interrupted time-series study over 20 years.
In a single tertiary hospital over 20 years, carbapenem preauthorization produced significant immediate and sustained reductions in carbapenem use without increasing 28-day mortality from nosocomial bacteremia. Usage intensity correlated positively with MRSA and carbapenem-resistant Gram-negative bacteremia prevalence.
Impact: Provides rare, long-horizon quasi-experimental evidence that formulary restriction can sustainably curb carbapenem exposure without harming patient outcomes and may mitigate resistance.
Clinical Implications: Hospitals can implement and maintain carbapenem preauthorization to reduce use while monitoring resistance and outcomes. ITS metrics (AUD) and resistance surveillance should be integrated into stewardship dashboards.
Key Findings
- Significant level (-0.367/100 patient-days; P=0.002) and trend (-0.014/100 patient-days; P=0.048) reductions in carbapenem AUD after preauthorization.
- No increase in 28-day mortality from nosocomial bacteremia following implementation.
- Carbapenem AUD positively correlated with MRSA (ρ=0.77), meropenem-resistant Pseudomonas aeruginosa (ρ=0.85), and Acinetobacter baumannii (ρ=0.80) bacteremia prevalence.
Methodological Strengths
- Two-decade interrupted time-series with clear pre- and post-intervention phases.
- Use of standardized antimicrobial use density and linkage to resistance and mortality endpoints.
Limitations
- Single-center design; concurrent infection control or stewardship changes may confound associations.
- Correlational analyses do not establish causality between carbapenem use and resistance trends.
Future Directions: Multi-center ITS or stepped-wedge studies to generalize findings; assess patient-level outcomes and microbiome/ecology effects; integrate rapid diagnostics to optimize carbapenem sparing.
BACKGROUND: Preauthorization of carbapenems is considered effective in reducing carbapenem overuse; however, long-term evaluations are lacking. AIM: We aimed to evaluate the long-term effects of judicious carbapenem restriction over almost two decades in a tertiary teaching hospital in Japan. METHODS: Interrupted time-series (ITS) analysis was applied to investigate changes in the level and trend of antimicrobial use density (AUD) of carbapenems by comparing the pre-intervention (2004 and 2005) and intervention (2006-2023) periods. Furthermore, this study explored the relationship between carbapenem AUD in hospitalized patients, the mortality rate of hospital-acquired bacteraemia, and the prevalence of bacteraemia caused by antibiotic-resistant nosocomial pathogens. FINDINGS: The ITS analysis demonstrated remarkably significant reductions in the level change of carbapenem AUD following the preauthorization (-0.367 per 100 patient days (95% confidence interval (CI), -0.131 to -0.603; P=0.002). In addition, the trend shift was -0.014 per 100 patient days (95% CI, -0.001 to -0.028; P=0.048). Following the implementation of carbapenem preauthorization, no increase in the 28-day mortality due to nosocomial bacteraemia was observed. Significant positive correlations were found between carbapenem AUD and the prevalence of meticillin-resistant Staphylococcus aureus (correlation coefficient (ρ) = 0.77 (P<0.001)), meropenem-resistant in Pseudomonas aeruginosa (ρ = 0.85 (P<0.001)), and Acinetobacter baumannii (ρ = 0.80 (P<0.001)). CONCLUSIONS: Long-term implementation of carbapenem preauthorization consistently proved to be effective with no adverse consequences for hospital epidemiology in a 20-year ITS analysis.
3. Salvianolic acid A ameliorates sepsis through inhibiting inflammation via binding STING and modulating TBK1/IRF3 signaling pathway.
In CLP sepsis and LPS-stimulated macrophage models, Salvianolic acid A improved survival, reduced inflammation, and preserved organ function by directly binding STING and inhibiting TBK1/IRF3 signaling. Target engagement was supported by CETSA and in silico docking/dynamics.
Impact: Identifies a small-molecule natural product that directly targets STING to modulate sepsis inflammation, bridging mechanism with a plausible therapeutic candidate.
Clinical Implications: While preclinical, STING pathway inhibition emerges as a tractable strategy; SAA or optimized analogs warrant translational development and safety/pharmacokinetic profiling for potential adjunctive sepsis therapy.
Key Findings
- In CLP mice, high-dose SAA improved survival from 18.75% to 55% and reduced lung neutrophil infiltration and histopathologic injury.
- SAA suppressed STING and TBK1/IRF3 activation in vivo and in vitro, lowering inflammatory cytokines and improving hepatorenal function.
- Target engagement demonstrated via CETSA, molecular docking, and molecular dynamics; SAA directly binds STING.
Methodological Strengths
- Combined in vivo CLP model outcomes with in vitro macrophage assays for mechanistic consistency.
- Direct target engagement assessment (CETSA) complemented by computational binding analyses.
Limitations
- Preclinical models; dosing, toxicity, and pharmacokinetics in humans are unknown.
- Potential off-target effects and species-specific STING biology may limit translation.
Future Directions: Define SAA pharmacology (PK/PD, safety) and optimize STING-binding analogs; evaluate efficacy in diverse sepsis models and consider combinatorial regimens with antibiotics and organ support.
Sepsis is a condition characterized by a systemic inflammatory response due to infection, resulting in numerous organ dysfunction. Salvianolic acid A (SAA) is a phenolic acid substance extracted from the plant Salvia miltiorrhiza Bunge, possessing antioxidant and anti-platelet aggregation properties. Although aberrant stimulator of interferon genes (STING) signaling is associated with sepsis, it is uncertain if SAA can influence this pathway to avert sepsis-induced organ injury. This study examined the antiseptic efficacy and biological mechanisms of SAA. The pharmacodynamics and mechanism of action of SAA in countering STING-induced inflammation during sepsis were investigated utilizing a cecal ligation and puncture (CLP) sepsis animal model. In vitro, RAW264.7 and THP-1 cells were preincubated with SAA for one hour before exposure to lipopolysaccharide (LPS). The molecular mechanism of SAA in the treatment of sepsis was examined by biochemical assays, pathological sections, enzyme-linked immunosorbent assay (ELISA), and western blot analysis. The association between SAA and its targets was examined via cellular thermal shift assay (CETSA), molecular docking, and molecular dynamics simulation analysis. The SAA intervention enhanced the survival rate of mice (18.75 % in the model group versus 55 % in the high-dose group) and dramatically reduced neutrophil infiltration in lung tissue as well as histological changes. It enhanced hepatorenal function and reduced inflammatory cytokines. Furthermore, the in vivo findings demonstrated that SAA could suppress the activation of the STING and TBK1/IRF3 signaling pathway, corroborating the in vitro results. SAA directly interacts with STING and regulates the TBK1/IRF3 signaling pathway to mitigate organ damage and inflammation caused by sepsis. It may serve as a viable therapeutic agent and prospective STING inhibitor.