Yearly ReportJan 1 – Dec 31, 2025
Sepsis, 2025 edition
We read 1360 papers and selected 10.
Summary
Sepsis research in 2025 underwent a decisive transition from syndrome-level treatment toward biologically stratified, time-dependent, and organ-specific precision medicine. Large human multi-omic studies demonstrated that infection source, age, immune state, and longitudinal molecular trajectories are major determinants of heterogeneity. Several studies established biomarker-to-mechanism-to-therapy chains involving immune collapse, endothelial injury, immunometabolism, pyroptosis, and mitochondrial dysfunction. Diagnostic research advanced from static risk prediction to deployable molecular testing, rapid host-response monitoring, pathogen-informed classification, and treatment-response assessment. Randomized trials showed that individualized physiological guidance, including capillary refill time, can improve patient-centered outcomes, while higher routine blood-pressure targets may cause harm in older patients. Methodologically, goal-directed multi-omics and predictive-enrichment frameworks offered new ways to design future sepsis trials around differential treatment response. The year's most important contributions were not guideline-driven interventions but discoveries that redefine sepsis as a collection of biologically distinct endotypes requiring repeated assessment. Most targeted therapies remain preclinical, making prospective validation, target engagement, and safety assessment essential.
Selected Articles
1. Single-cell multi-omic landscape reveals anatomical-specific immune features in adult and pediatric sepsis.
This comprehensive human reference study demonstrated that sepsis immune biology is shaped by anatomical infection source and age. It identified shared core features alongside distinct immune states and proposed an NR4A2-associated signature as a marker of heterogeneity.
Impact: It replaces the concept of a universal sepsis immune response with a human, source- and age-contextualized immune architecture. The breadth of integrated data makes it a reference framework for biomarker discovery and phenotype-enriched trials.
Clinical Implications: Source- and age-specific immune signatures could improve patient stratification and trial enrollment, but clinical utility, assay simplification, and prospective outcome benefit remain unproven.
Key Findings
- Integrated single-cell and multi-omic analyses identified infection-site-specific immune programs.
- Adult and pediatric sepsis shared core features but also exhibited distinct age-related states.
- An NR4A2-associated signature emerged as a candidate marker of immune heterogeneity.
Methodological Strengths
- Multi-platform profiling was performed in human adult and pediatric cohorts.
- The study connected cellular, receptor, transcriptomic, and plasma-protein data.
Limitations
- Most findings are observational and require prospective clinical validation.
- Complex multi-omic signatures may be difficult to translate into rapid routine assays.
Future Directions: Future work should develop compact source- and age-specific assays and test whether they improve predictive enrichment, treatment selection, and outcome assessment in prospective trials.
This human study integrated single-cell transcriptomics, T-cell and B-cell receptor sequencing, CITE-seq, bulk RNA sequencing, and plasma proteomics in adults and children with sepsis. It showed that infection source imprints distinct immune programs while preserving shared core features across ages.
2. Deriving consensus sepsis clusters via goal-directed subgroup identification in multi-omics study.
This study introduced goal-directed subgroup identification, deriving sepsis clusters according to differential treatment response rather than descriptive similarity alone. It offers a methodological foundation for predictive-enrichment trials.
Impact: It directly addresses treatment-effect heterogeneity, one of the central reasons previous sepsis trials have failed. The method could change how future trials define enrollment populations and test targeted interventions.
Clinical Implications: The framework could identify patients more likely to benefit from specific fluid strategies or host-directed therapies, but treatment assignment based on these clusters requires prospective randomized validation.
Key Findings
- Multi-omic data from 1,327 patients across 43 hospitals were integrated.
- Subgroups were optimized for differential treatment response rather than descriptive phenotype alone.
- External validation showed differential outcomes associated with fluid strategies and ulinastatin.
Methodological Strengths
- Large multicenter multi-omic dataset with longitudinal information.
- Subgroup discovery was explicitly linked to differential treatment benefit and externally validated.
Limitations
- Treatment-response signals remain observational and may reflect residual confounding.
- The multi-omic framework may be difficult to implement rapidly in routine care.
Future Directions: Prospective trials should compare predictive-enrichment designs with conventional enrollment and evaluate simplified assays that preserve treatment-response discrimination.
This framework integrated longitudinal transcriptomic, proteomic, metabolomic, and phenomic data from 1,327 patients across 43 hospitals. Unlike conventional clustering, it optimized subgroups for differential treatment response and externally validated survival differences related to fluid strategies and ulinastatin.
3. Longitudinal multi-omic signatures of ARDS and sepsis inflammatory phenotypes identify pathways associated with mortality.
This study moved sepsis phenotyping from single-time-point measurements to persistent molecular trajectories. Four externally validated signatures connected mortality with immune, metabolic, redox, and mitochondrial pathways.
Impact: It establishes that persistent biological states, rather than admission abnormalities alone, may define clinically meaningful sepsis endotypes and therapeutic windows.
Clinical Implications: Repeated molecular profiling may identify patients with active mitochondrial, metabolic, interferon, or redox dysfunction, but simplified assays and treatment trials are required.
Key Findings
- Four persistent mortality-associated molecular signatures were identified.
- The signatures persisted from day 0 to day 2 and converged on mitochondrial dysfunction.
- Findings were externally validated in an independent critically ill sepsis cohort.
Methodological Strengths
- Longitudinal metabolomic and transcriptomic sampling captured biological persistence.
- Independent external validation strengthened reproducibility.
Limitations
- The study primarily identifies associations rather than proving causal pathway effects.
- High-dimensional signatures require reduction before clinical implementation.
Future Directions: Future trials should use repeated molecular measurements to select patients for pathway-specific interventions and assess whether biological persistence predicts treatment response.
Longitudinal metabolomic and transcriptomic profiling identified four persistent mortality-associated molecular signatures involving innate immunity, glycolysis, fatty-acid oxidation, interferon suppression, redox biology, and mitochondrial dysfunction. The signatures were externally validated in an independent critically ill sepsis cohort.
4. A machine learning and centrifugal microfluidics platform for bedside prediction of sepsis.
This study translated a molecular deterioration signature into an automated bedside-compatible platform. It combined discovery, large external validation, and device development, addressing the time-sensitive need for early recognition of sepsis worsening.
Impact: It demonstrates a credible path from biomarker discovery to deployable molecular testing, a major methodological advance over retrospective prediction alone.
Clinical Implications: The platform could support earlier ICU referral and intensified monitoring, but prospective impact, workflow integration, cost, and antibiotic stewardship effects remain to be tested.
Key Findings
- A six-gene Sepset signature predicted deterioration within 24 hours.
- The classifier was externally validated in 3,178 patients.
- An automated centrifugal microfluidic RT-PCR platform achieved approximately 92–94% sensitivity and 89% specificity.
Methodological Strengths
- Large external validation cohort.
- Translation of the molecular classifier into an automated assay platform.
Limitations
- Clinical outcome benefit from assay-guided care was not tested prospectively.
- Performance may vary across institutions, populations, and preanalytic conditions.
Future Directions: Prospective implementation studies should evaluate turnaround time, alert-related behavior, antibiotic use, ICU transfer, and patient outcomes.
The study developed a six-gene Sepset signature for predicting clinical deterioration within 24 hours. It was derived from 586 samples, externally validated in 3,178 patients, and translated into an automated RT-PCR centrifugal microfluidic device with approximately 92–94% sensitivity and 89% specificity.
5. A conserved immune dysregulation signature is associated with infection severity, risk factors prior to infection, and treatment response.
This exceptionally large cross-cohort study linked pre-infection risk, immune state, prognosis, and treatment response through a conserved 42-gene signature. It provides a scalable human framework for treatment stratification.
Impact: It unifies host susceptibility and acute immune response in a single validated framework, challenging the separation between baseline risk and acute sepsis biology.
Clinical Implications: The signature may identify patients more likely to benefit from or be harmed by corticosteroids, but treatment-selection trials are required before clinical use.
Key Findings
- A 42-gene Severe-or-Mild signature was validated across 12,026 samples and 68 cohorts.
- The score associated pre-infection risk factors with severity and mortality.
- The signature identified differential associations with hydrocortisone response.
Methodological Strengths
- Exceptional sample size and cross-cohort validation.
- Integration of risk factors, molecular state, prognosis, and treatment response.
Limitations
- Treatment-response associations are not equivalent to randomized treatment effects.
- The signature requires simplification and prospective clinical utility testing.
Future Directions: Prospective trials should use the signature to enrich treatment groups and test whether immune-state-guided therapy improves benefit–risk balance.
Across 12,026 blood samples from 68 cohorts, the study validated a 42-gene Severe-or-Mild signature. The score linked age, sex, obesity, smoking, and comorbidity with severity, mortality, and differential hydrocortisone response, establishing a broad framework for immune-based patient stratification.
6. IGFBP6 orchestrates antiinfective immune collapse in murine sepsis via prohibitin-2-mediated immunosuppression.
This study established a complete human-association-to-mechanism-to-therapy chain for immune collapse. IGFBP6 impaired macrophage recruitment and bacterial killing through PHB2-linked signaling, while pathway rescue improved survival in mice.
Impact: It provides unusually mature translational evidence for immune collapse as a distinct, potentially treatable sepsis endotype.
Clinical Implications: IGFBP6 may support prognostic stratification and immunorestorative trial selection, but treatment timing must avoid worsening uncontrolled inflammation.
Key Findings
- IGFBP6 was associated with diagnosis and prognosis across human cohorts.
- IGFBP6 impaired PHB2–STAT1–CCL2 signaling and macrophage chemotaxis.
- PHB2 or Akt pathway rescue improved bacterial clearance and survival in mice.
Methodological Strengths
- Multicenter human cohorts were linked to mechanistic cellular and murine experiments.
- Therapeutic rescue experiments tested pathway causality.
Limitations
- The therapeutic findings remain preclinical.
- The optimal timing and safety of immune restoration are uncertain.
Future Directions: Future studies should validate IGFBP6-guided endotyping in prospective cohorts and test PHB2–STAT1 or Akt-directed treatment in carefully selected immune-collapse phenotypes.
IGFBP6 was associated with sepsis diagnosis and prognosis in multicenter human cohorts. It bound PHB2, impaired STAT1-driven CCL2 transcription and macrophage chemotaxis, suppressed Akt-dependent bactericidal activity, and was therapeutically rescued through PHB2–STAT1 or Akt pathways in septic mice.
7. Delaying pyroptosis with an AI-screened gasdermin D pore blocker mitigates inflammatory response.
This study introduced an execution-stage strategy for controlling pyroptosis. An AI-discovered peptide blocked gasdermin D pores while preserving upstream inflammatory signaling, reducing mortality and bystander activation in experimental models.
Impact: It shifts host-directed therapy from broad inflammatory suppression to selective interruption of a terminal execution step, offering a new therapeutic design principle.
Clinical Implications: Gasdermin D pore blockade could limit inflammatory injury while preserving some upstream host defense, but pharmacokinetics, immunogenicity, pathogen clearance, and treatment timing require study.
Key Findings
- SK56 directly blocked gasdermin D pores in macrophages and human leukocytes.
- SK56 improved survival in endotoxemia and CLP sepsis models.
- The peptide reduced bystander activation and cell death in human alveolar organoids.
Methodological Strengths
- AI-assisted discovery was followed by cellular, animal, and human organoid validation.
- The intervention targeted a defined execution step rather than upstream inflammation globally.
Limitations
- All efficacy evidence remains preclinical.
- Effects on antimicrobial defense and systemic pharmacology are unknown.
Future Directions: Future work should optimize peptide stability and delivery, establish target engagement, and test whether biomarker-defined pyroptosis phenotypes benefit preferentially.
The AI-screened peptide SK56 directly blocked gasdermin D pores without preventing upstream gasdermin D cleavage or IL-1β production. It reduced pyroptosis in human and murine cells, improved survival in endotoxemia and CLP models, and limited bystander immune activation in human alveolar organoids.
8. Efficacy of targeting high mean arterial pressure for older patients with septic shock (OPTPRESS): a multicentre, pragmatic, open-label, randomised controlled trial.
This randomized trial directly tested the assumption that older septic-shock patients should routinely receive higher arterial pressure targets. The higher-MAP strategy increased mortality and showed no beneficial subgroup.
Impact: Its importance is scientific rather than guideline-based: it demonstrated that escalating physiological targets can cause harm and that chronic hypertension does not automatically justify higher acute targets.
Clinical Implications: Routine high MAP targets should generally be avoided in older septic-shock patients unless individualized circumstances justify them, with close monitoring for vasopressor-related ischemia and arrhythmia.
Key Findings
- The trial stopped early because the high-MAP strategy increased harm.
- Ninety-day mortality was 39.3% with MAP 80–85 mmHg versus 28.6% with MAP 65–70 mmHg.
- No subgroup, including patients with chronic hypertension, benefited from the higher target.
Methodological Strengths
- Multicenter randomized clinical design with a patient-important mortality outcome.
- Pragmatic enrollment directly addressed a common physiological management assumption.
Limitations
- The trial was open-label and stopped early.
- Results may not generalize to younger patients or highly selected subgroups.
Future Directions: Further work should define individualized pressure targets using perfusion, chronic vascular disease, cardiac function, and organ-response phenotypes rather than age alone.
OPTPRESS randomized 518 patients aged 65 years or older with septic shock to MAP targets of 80–85 or 65–70 mmHg. The trial stopped early for harm: 90-day mortality was 39.3% versus 28.6%, with no beneficial subgroup identified.
9. Personalized Hemodynamic Resuscitation Targeting Capillary Refill Time in Early Septic Shock: The ANDROMEDA-SHOCK-2 Randomized Clinical Trial.
ANDROMEDA-SHOCK-2 provided high-level evidence that a simple bedside perfusion measure can guide individualized early resuscitation. Benefit was driven mainly by reduced duration of vital-organ support.
Impact: The trial operationalized precision physiology at the bedside and challenged purely pressure- or lactate-centered resuscitation strategies.
Clinical Implications: Structured CRT-guided care may reduce vasopressor and organ-support exposure, but training, standardization, patient selection, and outcome surveillance are required.
Key Findings
- The trial enrolled 1,467 patients from 86 centers in 19 countries.
- CRT-guided resuscitation produced a win ratio of 1.16.
- The benefit was driven mainly by shorter vital-organ support duration rather than definitive mortality reduction.
Methodological Strengths
- Large multinational randomized clinical trial.
- Patient-centered hierarchical outcome captured both survival and organ-support burden.
Limitations
- Mortality benefit was not definitive.
- CRT measurement and response protocols may vary between clinicians and settings.
Future Directions: Future studies should standardize CRT assessment, identify responsive phenotypes, and compare CRT with integrated perfusion and molecular endotyping.
This multinational randomized trial compared capillary-refill-time-targeted resuscitation with usual care in 1,467 patients across 86 centers. The personalized strategy improved a hierarchical 28-day patient-centered outcome, mainly through shorter vital-organ support duration rather than a clear mortality reduction.
10. Human proteome distribution atlas for tissue-specific plasma proteome dynamics.
This foundational atlas established a reference system for interpreting circulating proteins according to tissue and cellular origin. It provides the biological infrastructure needed to move sepsis monitoring beyond nonspecific inflammatory markers.
Impact: Rather than being a single diagnostic test, it is a reusable reference platform that can organize future organ-specific biomarker discovery across sepsis research.
Clinical Implications: Organ-specific panels may eventually identify kidney, liver, lung, endothelial, or immune injury, but assays must be simplified, accelerated, and prospectively linked to outcomes.
Key Findings
- A mass-spectrometry atlas mapped plasma proteins to 18 organs and eight major blood-cell types.
- Organ-enriched signatures were validated across six clinical cohorts, including sepsis.
- The framework supports organ-specific phenotyping of sepsis-associated injury.
Methodological Strengths
- Broad proteomic coverage with tissue- and cell-origin annotation.
- Validation across multiple independent clinical cohorts.
Limitations
- The atlas does not itself establish clinical utility or treatment benefit.
- Mass-spectrometry workflows may be difficult to deploy at the bedside.
Future Directions: Future research should convert atlas-derived signatures into rapid multiplex assays and test whether organ-resolved monitoring improves treatment selection and recovery assessment.
This study created a mass-spectrometry atlas linking circulating proteins to their tissue and cellular origins across 18 organs and major blood-cell populations. Disease- and organ-enriched panels were validated in six cohorts, including sepsis, providing a framework for organ-specific interpretation of plasma changes.