Oridonin as a Novel KDM5C Inhibitor Alleviates Clonal Hematopoiesis Induced Cardiac Aging via H3K4me3 Dependent SASP Suppression [RNA-seq]
We applied Tet2?/? bone marrow transplantation (BMT) mouse model to investigate the contribution of clonal hematopoiesis to cardiac aging. A transcriptome-guided small-molecule screening strategy was employed to identify potential therapeutic compounds. Target validation involved molecular docking, enzymatic inhibition, and surface plasmon resonance assays.  Genetic and pharmacological perturbation experiments were conducted to examine pathway involvement. Tet2?/?-BMT mice exhibited age-progressive myocardial fibrosis, inflammation, senescence, and functional decline. Oridonin reversed CHIP- and aging-associated transcriptional signatures and attenuated cardiac remodeling. Mechanistically, oridonin inhibited KDM5C histone demethylase. Downregulation of the pro-senescent factor S100A8 and suppression of SASP-associated inflammation were observed. Overall design: RNA-seq profiling was performed on cardiac tissues from wild-type and Tet2-deficient mice 12 months after bone marrow transplantation and treatment with Oridonin 2 months.