Sepsis Research Analysis
June 2025 sepsis research converged on precision immunology, actionable inflammatory circuits, and deployable diagnostics. A conserved 42-gene SoM signature linked baseline risk to infection severity and predicted steroid-related harm, while mechanistic studies exposed CK2–PGK1–NLRP3–USP14 inflammasome signaling and chromatin-based NFIL3 restraint. Organ-protection biology advanced with lactate-driven HADHA lactylation implicating SIRT1/3 in septic cardiomyopathy and a vagal brain–adrenal–lung c
Summary
June 2025 sepsis research converged on precision immunology, actionable inflammatory circuits, and deployable diagnostics. A conserved 42-gene SoM signature linked baseline risk to infection severity and predicted steroid-related harm, while mechanistic studies exposed CK2–PGK1–NLRP3–USP14 inflammasome signaling and chromatin-based NFIL3 restraint. Organ-protection biology advanced with lactate-driven HADHA lactylation implicating SIRT1/3 in septic cardiomyopathy and a vagal brain–adrenal–lung circuit suppressing lung inflammation. At the bedside, a six-gene Sepset microfluidic test and guidelines endorsing rapid blood-culture diagnostics with stewardship point to earlier, targeted care. Device/biomarker innovations (anti-thrombotic nano-coatings, EV-based coagulolytic balance) highlight phenotype-guided adjuncts.
Selected Articles
1. Lactylation of HADHA Promotes Sepsis-Induced Myocardial Depression.
The study maps extensive lysine lactylation in septic myocardium and shows that HADHA K166/K728 lactylation inhibits HADHA activity, impairs mitochondrial function, reduces ATP, and decreases cardiomyocyte contractility. SIRT1 and SIRT3 regulate these modifications, and site‑directed mutagenesis established causal links in LPS/CLP models and cell systems.
Impact: Defines a tractable post‑translational mechanism linking lactate signaling to septic cardiomyopathy and reframes lactate as an active modifier, highlighting the HADHA lactylation/SIRT1‑3 axis as a therapeutic target.
Clinical Implications: Motivates development of therapies targeting lactylation (e.g., SIRT1/3 modulators) or restoring HADHA function to prevent/treat septic myocardial depression and supports measuring cardiac lactylation in translational studies.
Key Findings
- 1,127 lysine lactylation sites mapped; 83 sites differentially lactylated in sepsis.
- HADHA K166/K728 lactylation inhibited enzymatic activity, impaired mitochondria/ATP, and reduced contractility.
- SIRT1/3 regulate HADHA lactylation; site‑directed mutagenesis established causality in LPS/CLP and cell models.
2. A conserved immune dysregulation signature is associated with infection severity, risk factors prior to infection, and treatment response.
Integrative analysis across 68 cohorts (12,026 samples) validates a conserved 42‑gene Severe‑or‑Mild (SoM) signature linking baseline risk factors to infection severity, predicting mortality and differential treatment response (including potential hydrocortisone harm), and modifiable by drugs/lifestyle.
Impact: Provides a robust, cohort‑validated immune score that enables precision endotyping, predicts who may benefit or be harmed by immunomodulators, and can reshape sepsis trial design.
Clinical Implications: SoM scoring could guide steroid use and immunomodulator selection, enrich clinical trials for likely responders/non‑responders, and be integrated into EHR workflows pending prospective validation.
Key Findings
- A 42‑gene SoM signature associates baseline risk (age, sex, obesity, smoking, comorbidity) with infection severity.
- SoM predicts mortality and identifies sepsis patients at risk of harm from hydrocortisone.
- The signature is modifiable by immunomodulatory drugs and lifestyle interventions across cohorts.
3. Inhibition of acute lung inflammation by a neuroimmune circuit induced by vagal nerve stimulation.
Selective afferent vagal nerve stimulation engages a brainstem–adrenal epinephrine circuit (nucleus tractus solitarius and rostral ventrolateral medulla) that suppresses TLR7‑driven macrophage activation and neutrophil lung recruitment; adrenalectomy or epinephrine blockade abolishes protection.
Impact: Defines a drug‑ and device‑tractable neuroimmune pathway to mitigate sepsis‑related lung inflammation, with clear intermediary mediators and targets.
Clinical Implications: Supports translational exploration of afferent‑selective VNS or downstream adrenergic modulation as adjuncts for sepsis/ARDS, requiring early human trials to define safety, selection, and parameters.
Key Findings
- Afferent (not efferent) VNS suppressed TLR7‑induced macrophage activation and neutrophil recruitment to lung.
- Protection required adrenal‑derived epinephrine and activation of NTS/RVLM brainstem nuclei.
- Loss of protection with adrenalectomy/epinephrine blockade highlights adrenergic mediators as druggable targets.
4. De novo assembly of nuclear stress bodies rearranges and enhances NFIL3 to restrain acute inflammatory responses.
Stress‑induced nuclear stress bodies reorganize SatIII loci and recruit transcriptional machinery to increase NFIL3 expression, dampening proinflammatory cytokines; activation in patient PBMCs correlates with survival, linking chromatin architecture to immune restraint in sepsis.
Impact: Reveals a chromatin‑based immunoregulatory axis (nSB–NFIL3) associated with patient survival, nominating biomarkers and targets for immunomodulation.
Clinical Implications: NFIL3/SatIII activation could serve as prognostic biomarkers of immune restraint; pharmacologic modulation of nSB components (e.g., HSF1/BRD4 interactions) warrants preclinical development.
Key Findings
- nSB assembly expands SatIII loci and enhances expression of nearby genes including NFIL3.
- NFIL3 upregulation increases chromatin accessibility and recruits HSF1/BRD4 to suppress proinflammatory cytokines.
- NFIL3/SatIII activation in sepsis patient PBMCs correlates with survival.
5. PGK1 phosphorylates NLRP3 and mediates inflammasome activation independent of its glycolytic activity.
CK2 phosphorylates PGK1 at S271 to switch on PGK1 kinase activity, which phosphorylates NLRP3 (S448/S449), recruits USP14, promotes deubiquitination, and activates the NLRP3 inflammasome, revealing a druggable CK2–PGK1–NLRP3–USP14 axis.
Impact: Identifies a phosphorylation cascade that directly activates NLRP3 independent of glycolysis, offering multiple intervention points to modulate inflammasome‑driven hyperinflammation.
Clinical Implications: Suggests targeting PGK1 kinase function or USP14 recruitment to dampen inflammasome‑mediated injury in sepsis; next steps include inhibitor development and validation in human tissues and sepsis models.
Key Findings
- CK2 phosphorylates PGK1 at S271, enabling PGK1 kinase activity.
- PGK1 phosphorylates NLRP3 at S448/S449, recruiting USP14 to promote deubiquitination and activation.
- Disrupting PGK1 kinase function or USP14 recruitment attenuated inflammasome activation and IL‑1β outputs.