Exploring METRNL as a novel biomarker in sepsis: diagnostic potential and secretion mechanism
Abstract Background Sepsis is a life-threatening condition with a high mortality rate in intensive care unit (ICU). However, rapid and accurate diagnostic criteria are still lacking. This pilot study explored the role of METRNL as a novel biomarker for sepsis by focusing on its diagnostic potential...
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BMC
2025-04-01
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| Series: | Journal of Intensive Care |
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| Online Access: | https://doi.org/10.1186/s40560-025-00780-4 |
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| author | Tian-Ying Xu Jing-Xin Zhao Ming-Yao Chen Zhu-Wei Miao Zhi-Yong Li Yong-Qing Chang Yu-Sheng Wang Chao-Yu Miao |
| author_facet | Tian-Ying Xu Jing-Xin Zhao Ming-Yao Chen Zhu-Wei Miao Zhi-Yong Li Yong-Qing Chang Yu-Sheng Wang Chao-Yu Miao |
| author_sort | Tian-Ying Xu |
| collection | DOAJ |
| description | Abstract Background Sepsis is a life-threatening condition with a high mortality rate in intensive care unit (ICU). However, rapid and accurate diagnostic criteria are still lacking. This pilot study explored the role of METRNL as a novel biomarker for sepsis by focusing on its diagnostic potential and rapid secretion mechanism. Methods METRNL levels were measured in cell and animal models of sepsis. Serum samples from 107 sepsis patients and 95 non-septic controls in ICU were collected. Diagnostic performance of METRNL, Procalcitonin (PCT) and C-reactive protein (CRP) were assessed using ROC analysis. Endothelial cell-specific Metrnl gene knockout mice (EC-Metrnl −/− mice) were used to identify the source of METRNL secretion. Chemical inhibitors and RNA interference were used to explore the secretion pathways. Results In lipopolysaccharide (LPS)-induced cell and mouse models of sepsis, METRNL levels significantly increased in a dose- and time-dependent manner. Similarly, in the cecal ligation and puncture mouse models, serum METRNL levels were elevated over time and correlated with sepsis severity. In animals, serum METRNL increased within 1 h post-modeling, preceding PCT and CRP. Clinically, sepsis patients had significantly higher serum METRNL levels. ROC analysis showed area under the curves [95% confidence intervals] of 0.943 [0.91–0.975] for METRNL, 0.955 [0.929–0.981] for PCT and 0.873 [0.825–0.921] for CRP. At the optimal cutoff value, METRNL (91.6%) exhibited relatively greater diagnostic specificity than PCT (88.4%) and CRP (69.5%). EC-Metrnl −/− reduced majority of serum Metrnl levels in sepsis mouse models. Inhibition of the endoplasmic reticulum-Golgi (ER-Golgi) pathway through chemical inhibitors or RNA interference significantly reduced METRNL levels in the supernatant of sepsis cell models compared to control groups. Similar results were obtained with Toll-like receptor 4 (TLR4) and ERK inhibitors. Conclusions This pilot study demonstrates that METRNL is a novel potential biomarker for sepsis with diagnostic capability comparable to that of PCT. Serum METRNL rapidly increased during the early phase of sepsis. Mechanistically, it mainly originates from the endothelium during sepsis, and TLR4-ERK signaling mediates the rapid secretion of METRNL via the classical ER-Golgi pathway in response to LPS stimulation. |
| format | Article |
| id | doaj-art-daa56d23650d439f89a1fb871a35a5ba |
| institution | DOAJ |
| issn | 2052-0492 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Intensive Care |
| spelling | doaj-art-daa56d23650d439f89a1fb871a35a5ba2025-08-20T03:10:09ZengBMCJournal of Intensive Care2052-04922025-04-0113111610.1186/s40560-025-00780-4Exploring METRNL as a novel biomarker in sepsis: diagnostic potential and secretion mechanismTian-Ying Xu0Jing-Xin Zhao1Ming-Yao Chen2Zhu-Wei Miao3Zhi-Yong Li4Yong-Qing Chang5Yu-Sheng Wang6Chao-Yu Miao7Department of Pharmacology, Second Military Medical University/Naval Medical UniversityDepartment of Pharmacology, Second Military Medical University/Naval Medical UniversityDepartment of Pharmacology, Second Military Medical University/Naval Medical UniversityDepartment of Pharmacology, Second Military Medical University/Naval Medical UniversityDepartment of Pharmacology, Second Military Medical University/Naval Medical UniversityDepartment of Critical Care Medicine, Changhai Hospital, Second Military Medical University/Naval Medical UniversityDepartment of Critical Care Medicine, Naval Medical Center of PLADepartment of Pharmacology, Second Military Medical University/Naval Medical UniversityAbstract Background Sepsis is a life-threatening condition with a high mortality rate in intensive care unit (ICU). However, rapid and accurate diagnostic criteria are still lacking. This pilot study explored the role of METRNL as a novel biomarker for sepsis by focusing on its diagnostic potential and rapid secretion mechanism. Methods METRNL levels were measured in cell and animal models of sepsis. Serum samples from 107 sepsis patients and 95 non-septic controls in ICU were collected. Diagnostic performance of METRNL, Procalcitonin (PCT) and C-reactive protein (CRP) were assessed using ROC analysis. Endothelial cell-specific Metrnl gene knockout mice (EC-Metrnl −/− mice) were used to identify the source of METRNL secretion. Chemical inhibitors and RNA interference were used to explore the secretion pathways. Results In lipopolysaccharide (LPS)-induced cell and mouse models of sepsis, METRNL levels significantly increased in a dose- and time-dependent manner. Similarly, in the cecal ligation and puncture mouse models, serum METRNL levels were elevated over time and correlated with sepsis severity. In animals, serum METRNL increased within 1 h post-modeling, preceding PCT and CRP. Clinically, sepsis patients had significantly higher serum METRNL levels. ROC analysis showed area under the curves [95% confidence intervals] of 0.943 [0.91–0.975] for METRNL, 0.955 [0.929–0.981] for PCT and 0.873 [0.825–0.921] for CRP. At the optimal cutoff value, METRNL (91.6%) exhibited relatively greater diagnostic specificity than PCT (88.4%) and CRP (69.5%). EC-Metrnl −/− reduced majority of serum Metrnl levels in sepsis mouse models. Inhibition of the endoplasmic reticulum-Golgi (ER-Golgi) pathway through chemical inhibitors or RNA interference significantly reduced METRNL levels in the supernatant of sepsis cell models compared to control groups. Similar results were obtained with Toll-like receptor 4 (TLR4) and ERK inhibitors. Conclusions This pilot study demonstrates that METRNL is a novel potential biomarker for sepsis with diagnostic capability comparable to that of PCT. Serum METRNL rapidly increased during the early phase of sepsis. Mechanistically, it mainly originates from the endothelium during sepsis, and TLR4-ERK signaling mediates the rapid secretion of METRNL via the classical ER-Golgi pathway in response to LPS stimulation.https://doi.org/10.1186/s40560-025-00780-4METRNLSepsisBiomarkerEndotheliumToll-like receptor 4Endoplasmic reticulum |
| spellingShingle | Tian-Ying Xu Jing-Xin Zhao Ming-Yao Chen Zhu-Wei Miao Zhi-Yong Li Yong-Qing Chang Yu-Sheng Wang Chao-Yu Miao Exploring METRNL as a novel biomarker in sepsis: diagnostic potential and secretion mechanism Journal of Intensive Care METRNL Sepsis Biomarker Endothelium Toll-like receptor 4 Endoplasmic reticulum |
| title | Exploring METRNL as a novel biomarker in sepsis: diagnostic potential and secretion mechanism |
| title_full | Exploring METRNL as a novel biomarker in sepsis: diagnostic potential and secretion mechanism |
| title_fullStr | Exploring METRNL as a novel biomarker in sepsis: diagnostic potential and secretion mechanism |
| title_full_unstemmed | Exploring METRNL as a novel biomarker in sepsis: diagnostic potential and secretion mechanism |
| title_short | Exploring METRNL as a novel biomarker in sepsis: diagnostic potential and secretion mechanism |
| title_sort | exploring metrnl as a novel biomarker in sepsis diagnostic potential and secretion mechanism |
| topic | METRNL Sepsis Biomarker Endothelium Toll-like receptor 4 Endoplasmic reticulum |
| url | https://doi.org/10.1186/s40560-025-00780-4 |
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