Promising therapeutic interventions for preserving endothelial glycocalyx integrity in sepsis: a systematic review

Endothelial Glycocalyx (eGCX) degradation is a major pathophysiological event in sepsis, contributing to endothelial dysfunction, vascular permeability, inflammation, microvascular thrombosis, and organ failure. Despite its importance, eGCX-targeted therapies are not currently incorporated into standard sepsis management. This systematic review summarized clinical and preclinical evidence on therapeutic and experimental strategies aimed at preserving or restoring eGCX integrity in sepsis. PubMed, Scopus, Web of Science, the Cochrane Library, and Google Scholar were searched through August 2026. Eligible human and animal studies evaluated eGCX-directed interventions in sepsis or experimental sepsis models. Outcomes included circulating biomarkers such as syndecan-1, heparan sulfate, and hyaluronan, microcirculatory measures including perfused boundary region, and structural assessment by microscopy. Risk of bias was assessed using RoB 2, SYRCLE, and ROBINS-I. Twenty-one studies were included, comprising 17 animal and 4 human studies. Interventions included ascorbic acid, sulodexide, doxycycline, activated protein C, heparin-based therapies, antithrombin, recombinant thrombomodulin, therapeutic plasma exchange, colivelin, liposomal nanocarriers of preassembled eGCX, and rhamnan sulfate. Several interventions reduced eGCX shedding, improved endothelial barrier or microvascular function, and, in some experimental models, preserved or restored eGCX ultrastructure. Overall, the eGCX represents a promising therapeutic target in sepsis; however, most evidence remains preclinical, and well-designed clinical studies using standardized eGCX outcomes are needed.