Serum EV-enriched proteomics reveals host-response subtypes and molecular similarity to organ dysfunction phenotypes in sepsis.
11 affiliations
- 1Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China.
- 2Department of Critical Care Medicine, Qilu Hospital, Shandong University, Jinan, China.
- 3Department of Critical Care Medicine, Dong E Hospital, Liaocheng, China.
- 4Department of Critical Care Medicine, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China.
- 5Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
- 6Department of Emergency Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- 7Provincial Key Laboratory of Precise Diagnosis and Treatment of Abdominal Infection, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
- 8School of Medicine, Shaoxing University, Shaoxing, China.
- 9Key Laboratory of Emergency and Trauma of Ministry of Education, Engineering Research Center for Hainan Biological Sample Resources of Major Diseases, The First Affiliated Hospital, Hainan Medical University, Haikou 571199, China.
- 10Endocrine and Metabolic Diseases Hospital of Shandong First Medical University, Shandong Institute of Endocrine and Metabolic Diseases, Jinan Key Laboratory of Translational Medicine on Metabolic Diseases, Jinan, China.
- 11Department of Critical Care Medicine, Public Health Clinical Center Affiliated to Shandong University, Shandong Public Health Clinical Center, Jinan, China.
Abstract
Introduction
Sepsis is a heterogeneous syndrome characterized by dysregulated host responses and diverse patterns of organ dysfunction. This study aimed to characterize serum extracellular vesicle (EV)-enriched proteomic heterogeneity in sepsis and assess whether proteomic subtypes identified among Sepsis-only patients showed molecular similarity to established organ dysfunction phenotypes.Methods
In this single-center observational study, serum EV-enriched preparations were analyzed from 250 patients with sepsis and 50 healthy controls enrolled between June 2021 and December 2022. ARDS and AKI status was determined at blood sampling, and patients with neither condition were classified as Sepsis-only. After proteomic quality control, 231 patients and 48 controls were included. Non-negative matrix factorization was used to identify proteomic subtypes among Sepsis-only patients. Centroid projection and clinically adjusted sensitivity analyses evaluated cross-sectional molecular similarity between these subtypes and established S-AKI, S-ARDS, and S-ARDS&AKI phenotypes. An exploratory elastic-net protein panel was derived, and the downstream supervised workflow was evaluated using repeated nested cross-validation conditional on the original subtype labels.Results
A total of 4,754 protein groups were quantified across 279 samples. Three proteomic subtypes were identified among 96 Sepsis-only patients. S1 showed less pronounced inflammatory features, whereas S2 was characterized by cellular immune and metabolic-stress pathways and S3 by humoral immune, complement/coagulation, hemostatic, and acute-phase processes. These molecular patterns were not fully captured by conventional severity scores. The organ dysfunction groups showed partial and reference-dependent molecular similarity to S3 after clinical adjustment. A hypothesis-generating 15-protein panel captured features shared by S3 and established organ dysfunction relative to S2.Conclusions
Serum EV-enriched proteomics revealed distinct host-response subtypes within the Sepsis-only group and contemporaneous molecular features shared with established organ dysfunction. These findings advance the molecular characterization of sepsis heterogeneity and provide a focused framework for future longitudinal and external validation.
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BibTeX
@article{ding2026serum,
title = {{Serum EV-enriched proteomics reveals host-response subtypes and molecular similarity to organ dysfunction phenotypes in sepsis.}},
author = {Rui Ding and Shihan Zhang and Xinyan Liu and Haiming Jiang and Chunting Wang and Zhongheng Zhang and Xinhua Li and Xuan Song},
journal = {Frontiers in medicine},
year = {2026},
month = oct,
doi = {10.3389/fmed.2026.1896167},
url = {https://europepmc.org/article/MED/42908901},
note = {CC BY},
}
RIS
TY - JOUR
TI - Serum EV-enriched proteomics reveals host-response subtypes and molecular similarity to organ dysfunction phenotypes in sepsis.
AU - Rui Ding
AU - Shihan Zhang
AU - Xinyan Liu
AU - Haiming Jiang
AU - Chunting Wang
AU - Zhongheng Zhang
AU - Xinhua Li
AU - Xuan Song
PY - 2026
DA - 2026/10/07
JO - Frontiers in medicine
DO - 10.3389/fmed.2026.1896167
UR - https://europepmc.org/article/MED/42908901
AB - Introduction Sepsis is a heterogeneous syndrome characterized by dysregulated host responses and diverse patterns of organ dysfunction. This study aimed to characterize serum extracellular vesicle (EV)-enriched proteomic heterogeneity in sepsis and assess whether proteomic subtypes identified among Sepsis-only patients showed molecular similarity to established organ dysfunction phenotypes.Methods In this single-center observational study, serum EV-enriched preparations were analyzed from 250 patients with sepsis and 50 healthy controls enrolled between June 2021 and December 2022. ARDS and AKI status was determined at blood sampling, and patients with neither condition were classified as Sepsis-only. After proteomic quality control, 231 patients and 48 controls were included. Non-negative matrix factorization was used to identify proteomic subtypes among Sepsis-only patients. Centroid projection and clinically adjusted sensitivity analyses evaluated cross-sectional molecular similarity between these subtypes and established S-AKI, S-ARDS, and S-ARDS&AKI phenotypes. An exploratory elastic-net protein panel was derived, and the downstream supervised workflow was evaluated using repeated nested cross-validation conditional on the original subtype labels.Results A total of 4,754 protein groups were quantified across 279 samples. Three proteomic subtypes were identified among 96 Sepsis-only patients. S1 showed less pronounced inflammatory features, whereas S2 was characterized by cellular immune and metabolic-stress pathways and S3 by humoral immune, complement/coagulation, hemostatic, and acute-phase processes. These molecular patterns were not fully captured by conventional severity scores. The organ dysfunction groups showed partial and reference-dependent molecular similarity to S3 after clinical adjustment. A hypothesis-generating 15-protein panel captured features shared by S3 and established organ dysfunction relative to S2.Conclusions Serum EV-enriched proteomics revealed distinct host-response subtypes within the Sepsis-only group and contemporaneous molecular features shared with established organ dysfunction. These findings advance the molecular characterization of sepsis heterogeneity and provide a focused framework for future longitudinal and external validation.
SN - 2296-858X
ER -