Mast Cell St8sia1 Is a Glyco-Epigenetic Checkpoint Driving Cardiac Remodeling
Changzuan Zhou, Lisheng Fu, Tianyou Yuan, Fangfang Li, Fanhuan Tang, Xiaoyu Wu, Yutong Ye, Longzhe Gao, Chenyang Jin, Qitong Zhang, Liang Xu, Shaowen Liu, Songwen Chen, Jun LiBACKGROUND:
Pathogenic immune-cardiac crosstalk underlies maladaptive remodeling in chronic heart failure, yet therapies directly targeting this axis are lacking. Glycoconjugates, which are crucial for signal transduction and extracellular matrix integrity, represent an underexploited therapeutic avenue. This study sought to define the role of glycoconjugate-metabolizing enzymes at the immune-cardiac interface and evaluate their translational potential.
METHODS:
We performed integrative analyses of bulk and single-cell RNA sequencing data from failing human and mouse hearts. Employing mouse models of pressure overload (transverse aortic constriction) and ischemia-reperfusion, we used global and mast cell (MC)-specific gene deletion, bone-marrow chimeras, and pharmacological neutralization. Mechanistic insights were gained through multiomics profiling, including RNA-seq, ATAC-seq, CUT&Tag, and proteomics.
RESULTS:
The ganglioside GD3 synthase, St8sia1, was selectively induced in cardiac MCs during pathological remodeling in both mice and humans. MC-specific or hematopoietic deletion of
CONCLUSIONS:
The MC-restricted St8sia1-GD3 axis functions as a glyco-epigenetic checkpoint driving maladaptive cardiac remodeling. Targeting this axis represents a translatable immunomodulatory strategy to prevent the progression to chronic heart failure.