Exploring METRNL as a novel biomarker in sepsis: diagnostic potential and secretion mechanism.

Summary

METRNL rises rapidly in experimental sepsis (within 1 hour) and is significantly elevated in ICU sepsis patients versus controls, with ROC AUC 0.943 comparable to procalcitonin and higher specificity at the optimal cutoff. Endothelial cells are the main source, with TLR4–ERK signaling mediating rapid secretion via the classical ER–Golgi pathway.

Key Findings

• In LPS and CLP models, serum METRNL increased in a dose- and time-dependent manner and within 1 hour, preceding PCT and CRP
• ICU sepsis patients (n=107) had significantly higher METRNL than controls (n=95); ROC AUC 0.943, comparable to PCT (0.955) and superior specificity at optimal cutoff
• Endothelial-specific Metrnl knockout and signaling studies showed endothelium as the main source and TLR4–ERK–ER/Golgi pathway mediating rapid secretion

Clinical Implications

METRNL could enable earlier sepsis recognition than PCT/CRP and help identify an endothelial injury phenotype, informing triage, monitoring, and biomarker-guided trials.

Limitations

• Single-center pilot with moderate sample size; external validation needed
• Diagnostic performance not evaluated in prospective emergency triage workflows

Future Directions

Prospective, multicenter diagnostic studies comparing METRNL with PCT/CRP and integration into multi-marker panels for endothelial sepsis endotypes.