Persistent Endothelial Glycocalyx Disruption in Sepsis: Translational Evidence for Melatonin‐Mediated Vascular Protection

Sepsis is a life-threatening syndrome driven by a dysregulated host response to infection, with endothelial dysfunction and glycocalyx disruption playing central roles in vascular failure. Despite growing recognition of the glycocalyx as a therapeutic target, its temporal dynamics and potential pharmacological modulation remain poorly understood. We performed a translational study combining longitudinal clinical observations in septic patients with mechanistic investigations in a murine cecal ligation and puncture (CLP) model. Plasma from patients was collected at intensive care unit admission and after clinical recovery to assess inflammatory mediators, coagulation parameters, and glycocalyx-related biomarkers. In parallel, the CLP model evaluated systemic and tissue-specific glycocalyx alterations and the effects of injectable melatonin. Acute sepsis induced marked alterations in multiple glycocalyx-related biomarkers in patients, with several changes persisting despite normalization of organ dysfunction and standard inflammatory indices, indicating ongoing endothelial injury and repair. In the CLP model, sepsis reproduced these alterations, while melatonin treatment significantly attenuated systemic cytokine responses and partially restored circulating and tissue glycocalyx components in an organ- and gene-specific manner. These results highlight persistent, dynamic glycocalyx disruption as a key driver of sepsis pathology and support pharmacological stabilization of the glycocalyx as a promising therapeutic strategy. Melatonin emerges as a potential endothelial-protective agent capable of promoting vascular recovery and homeostasis, providing translational insight for interventions targeting microvascular integrity in sepsis.