Daily Sepsis Research Analysis
Mechanistic and therapeutic advances in sepsis include a Cell Reports study revealing a non-glycolytic kinase role of PGK1 that directly activates the NLRP3 inflammasome, a Cochrane review showing corticosteroids probably reduce 28-day and in-hospital mortality in sepsis, and preclinical evidence that persistent S1P1 activation via a novel agonist (3,4-cPP) ameliorates CLP-induced sepsis through SIRT1. Together, these works span molecular targets to practice-informing evidence.
Summary
Mechanistic and therapeutic advances in sepsis include a Cell Reports study revealing a non-glycolytic kinase role of PGK1 that directly activates the NLRP3 inflammasome, a Cochrane review showing corticosteroids probably reduce 28-day and in-hospital mortality in sepsis, and preclinical evidence that persistent S1P1 activation via a novel agonist (3,4-cPP) ameliorates CLP-induced sepsis through SIRT1. Together, these works span molecular targets to practice-informing evidence.
Research Themes
- Inflammasome regulation and immunometabolism in sepsis
- Adjunctive therapies for sepsis (corticosteroids, S1P1 agonism)
- Translational bridges from mechanisms to clinical practice
Selected Articles
1. PGK1 phosphorylates NLRP3 and mediates inflammasome activation independent of its glycolytic activity.
This study uncovers a non-glycolytic kinase function of PGK1: CK2 phosphorylates PGK1 at S271, switching it to phosphorylate NLRP3 at S448/S449, which recruits USP14 to deubiquitinate and activate the NLRP3 inflammasome. The work provides a mechanistic link between metabolism and innate immune activation, independent of glycolytic flux.
Impact: Identifying PGK1 as a kinase for NLRP3 activation reveals a druggable signaling axis (CK2–PGK1–NLRP3–USP14) that could be targeted to modulate hyperinflammation in sepsis and other inflammasome-driven diseases.
Clinical Implications: While preclinical, this mechanism suggests therapeutic strategies such as inhibiting PGK1’s kinase activity, preventing NLRP3 S448/S449 phosphorylation, or disrupting USP14 recruitment to dampen inflammasome activation in hyperinflammatory states.
Key Findings
- CK2 phosphorylates PGK1 at S271, serving as a molecular switch for PGK1 kinase function.
- PGK1 phosphorylates NLRP3 at S448/S449, recruiting USP14 to promote NLRP3 deubiquitination and activation.
- PGK1’s regulation of NLRP3 is independent of its glycolytic enzymatic activity and is engaged upon LPS stimulation.
Methodological Strengths
- Mechanistic dissection of a novel phosphorylation cascade linking CK2, PGK1, and NLRP3 with site-specific mapping.
- Integration of kinase signaling and ubiquitin biology (USP14 recruitment) to explain inflammasome activation.
Limitations
- Abstract indicates LPS-driven models; extent of in vivo validation in sepsis models and human tissues is not detailed.
- No therapeutic modulation or inhibitor studies are presented to demonstrate druggability.
Future Directions: Test PGK1/NLRP3 phosphorylation blockade in in vivo sepsis models, develop selective PGK1 kinase inhibitors, and validate S271/S448-S449 phosphorylation as biomarkers in human sepsis.
Glycolysis is a critical player in the inflammatory response. Phosphoglycerate kinase 1 (PGK1) is an essential enzyme in the glycolysis pathway. However, little is known about its role in inflammatory response. In this study, we report PGK1 as a kinase that directly regulates NLRP3 inflammasome activation in response to lipopolysaccharide (LPS) stimulation via non-glycolytic function. We identified a novel phosphorylation modification of PGK1 at S271, mediated by protein kinase CK2. Importantly, phosphorylation at S271 serves as a molecular switch that activates PGK1's kinase function, activating it to phosphorylate NLRP3. This PGK1-mediated phosphorylation at S448/S449 of NLRP3 subsequently recruits USP14 to facilitate NLRP3 deubiquitination, thereby promoting NLRP3 inflammasome activation. Using PGK1
2. Corticosteroids for treating sepsis in children and adults.
Across 87 RCTs including 24,336 participants, corticosteroids probably reduce 28-day mortality (RR 0.89) and in-hospital mortality, and may shorten ICU/hospital stay, without clear increase in superinfection; muscle weakness remains uncertain. Evidence is very uncertain regarding continuous infusion versus bolus administration.
Impact: This high-quality synthesis consolidates the mortality benefit of corticosteroids in sepsis and informs guideline updates while clarifying safety signals and knowledge gaps in dosing strategies.
Clinical Implications: Consider corticosteroids (e.g., hydrocortisone) in septic patients, recognizing probable short-term mortality benefit and potential reduction in length of stay; monitor for neuromuscular weakness. There is no clear evidence favoring continuous infusion over bolus.
Key Findings
- Corticosteroids probably reduce 28-day mortality (RR 0.89, 95% CI 0.84–0.95; moderate-certainty).
- In-hospital mortality is probably reduced; long-term mortality shows little to no difference.
- ICU and hospital length of stay may be shortened; risk of superinfection shows little to no difference; muscle weakness is uncertain.
- Continuous infusion vs intermittent bolus effects are very uncertain across outcomes.
Methodological Strengths
- Comprehensive search across multiple databases with GRADE assessment and risk-of-bias evaluation.
- Large aggregate sample size with inclusion of pediatric and adult populations; acquisition of unpublished data.
Limitations
- Significant heterogeneity across trials led to downgrading certainty for key outcomes.
- Very low-certainty evidence for continuous infusion vs bolus comparisons limits dosing guidance.
Future Directions: Incorporate newly identified trials (post-2024 search), refine pediatric-specific estimates, and optimize steroid dosing and duration with pragmatic RCTs.
BACKGROUND: Sepsis occurs when an infection is complicated by organ failure. Sepsis may be complicated by impaired corticosteroid metabolism. Thus, providing corticosteroids may benefit patients. This is an update of a review originally published in 2004 and previously updated in 2010, 2015 and 2019. OBJECTIVES: To examine the benefits and harms of corticosteroids in children and adults with sepsis. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, ClinicalTrials.gov, ISRCTN and the WHO Clinical Trials Search Portal on 31 December 2023. In addition, we conducted reference checking and citation research, and contacted study authors, to identify additional studies as needed. We updated this search in December 2024, but these results have not yet been incorporated. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of corticosteroids versus placebo or usual care (antimicrobials, fluid replacement and vasopressor therapy as needed) in children and adults with sepsis. We also included RCTs of continuous infusion versus intermittent bolus of corticosteroids. DATA COLLECTION AND ANALYSIS: We used the same methods in comparisons of corticosteroids versus placebo or usual care, and of continuous infusion versus intermittent bolus administration of corticosteroids. The primary outcome was all-cause mortality at 28 days. The most critical secondary outcomes were (i) all-cause mortality in the long term (last follow-up from 90 days to one year) and in the hospital; (ii) length of stay in the intensive care unit and in hospital; (iii) adverse effects, i.e. superinfection and muscle weakness (within 28 days). All review authors screened and selected studies for inclusion. One review author extracted data, which was checked by the others, and by the lead author of the primary study when possible. For this update, we used Covidence software for screening and selection of studies and abstraction of data by paired review authors, with discrepancies resolved by a third review author. We obtained unpublished data from the authors of some trials. We assessed the risk of bias in trials using the Cochrane risk of bias tool (RoB 1) and applied GRADE to assess the certainty of evidence. The review authors did not contribute to the assessment of eligibility or risk of bias, nor to data extraction, for the trials they had participated in. MAIN RESULTS: We included 87 trials (24,336 participants), of which six included only children, two included children and adults, and the remaining trials included only adults. Seventeen additional trials are ongoing and will be considered in future versions of this review. We judged 25 trials as being at low risk of bias. Corticosteroids versus placebo or usual care Compared to placebo or usual care, corticosteroids probably reduce 28-day mortality (risk ratio (RR) 0.89, 95% confidence interval (CI) 0.84 to 0.95; 72 trials, 22,915 participants; moderate-certainty evidence). We downgraded the certainty of evidence for this outcome from high to moderate for inconsistency (significant heterogeneity across trial results). Corticosteroids may result in little to no difference in long-term mortality (RR 0.97, 95% CI 0.91 to 1.03; 12 trials, 8468 participants; low-certainty evidence) and probably reduce in-hospital mortality (RR 0.90, 95% CI 0.84 to 0.97; 40 trials, 17,459 participants; moderate-certainty evidence). Corticosteroids may reduce length of intensive care unit (ICU) stay for all participants (mean difference (MD) -0.86 days, 95% CI -1.67 to -0.05; 25 trials, 8069 participants; low-certainty evidence) and may reduce length of hospital stay for all participants (MD -1.09 days, 95% CI -1.85 to -0.34; 31 trials, 16,954 participants; low-certainty evidence). The evidence is uncertain about the effect of corticosteroids on the risk of muscle weakness (RR 1.09, 95% CI 0.78 to 1.53; 7 trials, 6729 participants; very low-certainty evidence). Corticosteroids may result in little to no difference in the risk of superinfection (RR 0.96, 95% CI 0.86 to 1.07; 36 trials, 7961 participants; low-certainty evidence). Continuous infusion of corticosteroids versus intermittent bolus Four trials reported data for this comparison, and the certainty of evidence for all outcomes was very low. We are uncertain about the effects of continuous infusion of corticosteroids compared with intermittent bolus administration on 28-day mortality (RR 1.03, 95% CI 0.81 to 1.32; 3 trials, 310 participants). We downgraded the certainty of evidence to very low due to high risk of bias in all except one trial and due to imprecision. Compared to bolus administration, we are uncertain of the effects of continuous infusion of corticosteroids on long-term mortality (RR 1.36, 95% CI 1.02 to 1.81; 1 trial, 70 participants; very low-certainty evidence), in-hospital mortality (RR 0.92, 95% CI 0.71 to 1.19; 3 trials, 352 participants; very low-certainty evidence), ICU length of stay amongst all participants (MD -0.56 days, 95% CI -3.44 to 2.32; 4 trials, 422 participants; very low-certainty evidence), hospital length of stay amongst all participants (MD -0.21 days, 95% CI -4.72 to 4.30; 4 trials, 422 participants; very low-certainty evidence), risk of muscle weakness (RR 0.89, 95% CI 0.13 to 5.98; 1 trial, 70 participants; very low-certainty evidence) and risk of superinfection (RR 1.12, 95% CI 0.37 to 3.33; 2 trials, 193 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Moderate-certainty evidence indicates that corticosteroids probably reduce 28-day, 90-day and hospital mortality amongst patients with sepsis. Corticosteroids may shorten ICU and hospital length of stay (low-certainty evidence). There may be little or no difference in the risk of superinfection. The risk of muscle weakness is uncertain. The effects of continuous versus intermittent bolus administration of corticosteroids are uncertain.
3. Persistent Activation of Sphingosine-1-Phosphate Receptor 1 by Phytosphingosine-3,4-Cyclic Phosphate Ameliorates Sepsis by Inhibiting Hyperinflammation and Vascular Hyperpermeability.
A novel S1P1 agonist, phytosphingosine-3,4-cyclic phosphate (3,4-cPP), persistently activates S1P1 without internalization, upregulates SIRT1 in macrophages and endothelial cells, lowers IL-6/TNF-α, and reduces endothelial permeability, conferring protection in CLP-induced sepsis. Conditional SIRT1 knockout abrogates benefit, implicating the S1P1–SIRT1 axis.
Impact: Introduces a drug-like agonist that persistently activates S1P1 and delineates a mechanistic S1P1–SIRT1 pathway to blunt sepsis hyperinflammation and vascular leak, offering a translational adjunctive therapy concept.
Clinical Implications: Supports development of S1P1-targeted adjuncts to reduce cytokine storm and endothelial leak in sepsis; requires safety, dosing, and efficacy studies in large animals and humans, given class-specific concerns (e.g., bradycardia, lymphopenia).
Key Findings
- 3,4-cPP persistently activates S1P1 without receptor internalization.
- S1P1 activation upregulates SIRT1 in macrophages and endothelial cells, lowering IL-6 and TNF-α.
- 3,4-cPP reduces endothelial permeability and protects against CLP-induced sepsis; SIRT1 conditional knockout abrogates these benefits.
Methodological Strengths
- Use of a clinically relevant CLP sepsis model with mechanistic validation via SIRT1 conditional knockout.
- Multi-compartment assessment (immune and endothelial) with cytokine and permeability readouts.
Limitations
- Preclinical mouse data without human validation; sample sizes and survival effect sizes are not specified in the abstract.
- Potential class-related safety issues of S1P pathway modulation are not addressed.
Future Directions: Define pharmacokinetics/pharmacodynamics and safety, optimize dosing, test in large-animal sepsis models, and progress to early-phase clinical trials with endothelial and inflammatory biomarkers.
Sepsis is a life-threatening disease characterized by multiorgan dysfunction caused by an abnormal immune response to microbial infection. Sphingosine-1-phosphate (S1P) levels are significantly lower in patients with sepsis and are negatively correlated with the severity of sepsis. However, whether the S1P signaling pathway is a target for sepsis treatment remains unknown. Here, we show that our newly synthesized phytosphingosine-3,4-cyclic phosphate (3,4-cPP), a functional agonist of S1P receptor 1 (S1P1), exerts a strong protective effect against severe cecal ligation and puncture (CLP)-induced sepsis. 3,4-cPP persistently activates S1P1 without inducing internalization. 3,4-cPP upregulates SIRT1 expression in macrophages and endothelial cells via S1P1 activation. Additionally, 3,4-cPP decreases serum levels of proinflammatory cytokines, including IL-6 and TNF-α, and inhibits endothelial permeability in CLP-induced septic mice. Conditional knockout of SIRT1, an NAD