O-GlcNAcylation: A bridge for regulating the function of the “heart-kidney-bone axis”

The three major organ systems of heart, kidney and bone are highly correlated in physiology and pathology. They form the “heart-kidney-bone axis” together. The typical clinical manifestations of this axis include the deterioration of heart and kidney function, reflected by cardiorenal syndrome, renal bone disease, and cardiovascular calcification contained in chronic kidney disease-mineral bone disorder (CKD-MBD). However, the core molecular mechanism that regulates this axis has not been fully understood. O-linked N-acetylglucosamine (O-GlcNAc) glycosylation modification is a dynamic, reversible and highly conserved protein post-translational modification (PTM). It integrates body nutrition and stress signals via the hexosamine biosynthesis pathway (HBP), extensively participates in fine cellular function regulation, and plays an essential role in the progression of heart, kidney and bone diseases. This review systematically summarizes the role and multidimensional regulatory network characteristics of O-GlcNAcylation in heart, kidney and skeletal systems. It focuses on exploring its cross-organ regulatory mechanism in the “heart-kidney-bone axis”, and aims to provide new ideas for the mechanism analysis and targeted therapy of comorbidities. • Proposing O-GlcNAc glycosylation modification as a molecular bridge integrating metabolic signals and inter organ regulation.