Chernykh, A.Sumer-Bayraktar, Z.Lee, J.H.Meyer, E.J.Torpy, D.J.Thaysen-Andersen, M.2025-07-092025-07-092025Glycobiology, 2025; 35(4):cwaf013-1-cwaf013-100959-66581460-2423https://hdl.handle.net/2440/145808Corticosteroid-binding globulin (CBG) is a serum glycoprotein that binds and delivers anti-inflammatory cortisol to inflammatory sites through neutrophil elastase-mediated proteolysis of an exposed reactive centre loop (RCL) on CBG. Timely and tissue-specific delivery of cortisol is critical to alleviate inflammation including in life-threatening septic shock conditions. Herein, we firstly summarise our recently published report of functional RCL O- and N-glycosylation events of serum CBG (Chernykh, J Biol Chem, 2023). A key finding of that published work was the LC–MS/MS-based discovery of RCL O-glycans at Thr342 and Thr345 of serum CBG and their inhibitory roles in neutrophil elastase-mediated RCL proteolysis. While these observations are of significance as they implicate RCL O-glycosylation as a potential regulator of cortisol delivery, the link to septic shock remains unexplored. To this end, we used a similar LC–MS/MS approach to profile the RCL O-glycosylation of CBG purified from serum of twelve septic shock patients. Serum CBG from all patients exhibited RCL O-glycosylation comprising (di)sialyl T (NeuAc₁-₂Gal₁GalNAc₁) core 1-type O-glycan structures decorating exclusively the Thr342 site. Importantly, relative to less severe cases, individuals presenting with the most severe illness displayed elevated RCL O-glycosylation upon ICU admission, suggesting a previously unknown link to septic shock severity. Overall, we have elucidated the coordinated RCL N- and O-glycosylation events of serum CBG, which improve our understanding of molecular mechanisms governing the timely and tissue-specific delivery of cortisol to inflammatory sites. This work provides clues to molecular aberrations and disease mechanisms underpinning septic shock.en©The Author(s) 2025. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comHydrocortisoneTranscortinCBG; cortisol; glycosylation; reactive centre loop; septic shock.HydrocortisoneTranscortinJournal article10.1093/glycob/cwaf013731626Meyer, E.J. [0000-0002-7450-5808]Torpy, D.J. [0000-0002-5069-0981]